Taste masked pharmaceutical composition

ABSTRACT

Taste masked multi-layered particles include an inert core, one or more coating layer(s) comprising a pharmaceutically active ingredient and a binder, an intermediate coating layer (seal coating) free from a low molecular weight water-soluble ionic compound and including a water-soluble pharmaceutical film-forming compound selected from (i) HPMC and PEG or (ii) PVP, and an outer coating layer (final or taste masking coating) free from a low molecular weight water-soluble ionic compound and comprising (i) a poly(meth)acrylate or (ii) a mixture including 60-90% (w/w) EC and 10-40% (w/w) HPMC, where the pharmaceutically active ingredient is water-soluble and includes either at least one basic group and/or a bitter taste. Further disclosed are methods for the production of such particles and pharmaceutical compositions including such particles.

FIELD OF THE INVENTION

The present invention relates to the manufacture of pharmaceuticalcompositions, especially for the preparation of formulationintermediates of active ingredients for pharmaceutical compositions.

BACKGROUND OF THE INVENTION

The manufacture of pharmaceutical compositions comprises severalaspects, one of them being the task of providing active ingredients inan appropriate form. Ideally active ingredients, especially those havingan unpleasant taste, are prepared so that the patient taking apharmaceutical composition does not refrain from doing so because of theunpleasant taste.

Taste masking is useful in the field of veterinary medicine becauseanimals are sensitive to taste, and unlike humans, cannot be “persuaded”by reasoned argument to swallow a composition that the animal perceivesas unpleasant. In most cases pharmaceutical compositions for animalsinclude specific flavors, e.g. meat flavor for predominantly carnivorousanimals. Such flavors, however, simply add to the taste of the medicineitself and serve to cover the taste perception, but in many cases addingflavor is not sufficient if the taste of the compound is stillperceivable by the animal patient. On the contrary, bitter or otherwiseunpleasant compounds intended for oral application in veterinarymedicine are preferably hidden away, especially from the animal'sperception. Such taste masking is a severe restriction for the use ofpharmaceutical compositions in veterinary medicine.

In addition, the release of the active ingredient of a pharmaceuticalcomposition to the patient's body needs to be optimized with respect tothe envisaged activity of the compound. This optimization applies tooral compositions, especially those that are desired to dissolve, e.g.in the stomach, shortly after administration.

The problem of an adequate formulation of an active ingredient has to besolved for every pharmaceutical composition. It occurs for all activecompounds used for all sorts of medical treatments. In particular, oraldosage forms are confronted with the need of masking a taste when theaddition of flavoring agents alone is not sufficient to mask theunpleasant taste of the active compound.

In pharmaceutics while developing a solid dosage form, a taste isusually masked by applying a film coat consisting of a taste neutralpolymer onto a whole tablet. But this technique does not solve theproblem discussed here, especially for the treatment of predominantlycarnivorous animals because a film-coated tablet is usually of neutralsmell which is not attractive to the animal and therefore less likely tobe ingested voluntarily. Further, many animals, especially cats, havethe habit of breaking down their food by biting on it several times, andthereby, destroying the masking film and releasing the unpleasant taste.Similarly, a film-covered tablet cannot be divided in parts to optimizethe individual dosage without destroying the masking film. In somecases, a tablet is not the appropriate dosage form, especially whenthere is a necessity for precise dose adjustment that is easier byemploying a liquid dosage form. Accordingly this issue also applies toliquid pharmaceutical formulations.

Metabolic disorders like diabetes can in principle be treated by theoral application of respective pharmaceutical compositions, e.g. thosethat comprise DPP IV-inhibitors. Inhibitors of DPP IV belonging to thestructural class of xanthine derivatives are disclosed generically by WO02/068420 A1.

The compound1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthineis described explicitly in WO 2005/085246 A1, example 1(52). Its mono-and di-hydrochloride, as well as, polymorphs of the free base and thehydrochlorides are described in WO 2007/014886 A1. These applicationsdisclose methods for the chemical synthesis of this compound along withits salts, hydrates and other forms.

International patent application PCT/EP2011/054440 pertains topharmaceutical compositions comprising the compound1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinein the form of the free base, as well as, every other chemical form,including solvates, prodrug esters, stereoisomers, and salts (especiallythe monohydrochloride) for the treatment of a metabolic disorder ormetabolic disease of a predominantly carnivorous non-human animal likedog (canine) or cat (feline). Such disorders are selected fromketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulinresistance, obesity, hyperglycemia, hyperinsulinemia, elevated bloodlevels of fatty acids, hyperlipidemia and/or elevated blood levels ofglycerol, Syndrome X (metabolic syndrome), atherosclerosis, inflammationof the pancreas and/or inflammation of adipose tissue, preferablyketoacidosis, pre-diabetes and/or diabetes mellitus type 1 or type 2,more preferred diabetes mellitus type 2.

This application discloses an oral application of the active ingredient.However, it does not teach a specific granulation or manufacturingtechnique for the active compound. An appropriate taste masking of thecompound is still desirable, especially because of the bitter taste ofthe substance.

Other examples of active ingredients intended for an oral applicationare those for the treatment of heart diseases. Heart diseases includefor example coronary heart diseases, cardiomyopathies, cardiovasculardiseases, heart failure, hypertensive heart diseases or valvular heartdiseases. These different classes of heart diseases are treated withtherapies or combined therapies and hence with different classes ofcompounds. Therapies include administering one or more ACE inhibitors,beta-blockers, angiotensine II receptor antagonists, diuretics,Ca²⁺-sensitising agents, antiarrthythmic agents, cardioac glycosides orbradycardic agents such as i_(F)-channel blockers.

European patent application EP 224794 A2 discloses a number of cyclicamine derivatives falling under a general formula including theirchemical synthesis, the molecule3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onbeing one of them. They are described to exert a heart frequencelowering activity in rat. Its enationamer with the chemical name(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on carries the international nonproprietary name (INN) cilobradine.The derived hydrochloride can be named as cilobradine hydrochloride.Cilobradine and its hydrochloride are highly water-soluble.

WO 01/78699 A2 discloses the use of structurally diverse bradycardiacsubstances such as calcium channel blockers, beta-receptor blockers andi_(f)-channel blockers, optionally in combination with cardio-activesubstances, for treating and even inducing the regression of myocardialdiseases associated with hypertrophy, in particular for treatingideopathic hypertrophic cardiomyopathies (HCM) in humans and domesticanimals. One of the i_(f)-channel blockers that is mentioned iscilobradine, which has a bitter taste. WO 01/78699 A2 discloses that theactive ingredient, such as cilobradine, can be provided in the form of asimple mixture with other ingredients and assembled in a capsule, in theform of a granulate or a dragée, based on the same granulate, coatedwith a mixture of corn starch and sugar. Solutions comprising the activeingredient dissolved in a liquid are also disclosed.

Cilobradine is further disclosed to be useful for the treatment orprevention of heart failure, by EP 1362590 A1. Whereas the examples ofthis publication disclose the application of the active ingredient byinjection, the disclosure also describes drinking solutions which areclearly easier to handle by a patient. Another use of bradycardicsubstances, like i_(f)-channel blockers and especially cilobradine, isdisclosed by EP 1762179 A1, which discloses that these substances can beused for improving diagnostic quality in echocardiography.

Further pharmaceutically active compounds which are advantageouslyapplied orally and confronted with the need and/or desire of maskingtheir taste are per se known to the skilled person.

To address the problem of taste-masking an active ingredient(s) that isincorporated into pharmaceutical compositions, specific techniques haveevolved in the state of the art. These are mostly coating techniquesthat coat, i.e. cover, the active ingredient by another substance inwhich the other substance serves as a physicochemical barrier againstthe evaporation, dissolution, or diffusion of the active ingredient. Thecoated particle is used as one component of the complete pharmaceuticalcomposition. The barrier function of the protective coating should lastas long as the pharmaceutical composition is stored and/or theingredient could otherwise be perceived by the patient. Multiphasesystems can be used to keep the active ingredient in a separate phasefrom the remainder of the composition. However, the pharmaceuticalcomposition should dissolve or become permeable as soon as necessary forthe ingredient to become active.

One technique is to prepare particles comprising the active ingredientby using a granulation step followed by a coating step. EP 292840 A2exemplifies this technique in its example I (¶¶ 1444-1448) where theactive ingredient is mixed with starch, sugar, polyvinylpyrrolidon andmagnesium stearate, and the mixture is subsequently pressed andprocessed into granules. These granules are then mixed with anothercomponent and pressed into tablets. Such a tablet is finally describedto be coated by a mixture of sugar and talc, thus resulting in aso-called dragee (example II, ¶¶ 1449-1451).

EP 409254 A1 addresses the dissolution aspect of granular particlescomprising a core and a film layer coating the core. The disclosed corescomprise the active substance and a water -swelling agent; and the filmlayer contains at least ethylcellulose and a substance selected fromethylcellulose, HPMC (hydroxypropylmethylcellulose), MC(methylcellulose), L-HPC (low substituted hydroxypropylcellulose) andPVP (polyvinyl pyrrolidone). The specification describes that based onthe taste perception by humans it was desired to reach a masking time ofat least 20 s. The disclosed coatings allowed a masking time of 1 to at57 s.

Coatings comprised of two or more coating layers, especially doublelayers, are also known. For example, the U.S. Pat. No. 4,874,613 teachescoating an inert inner core containing the active substance with a firstlayer surrounding the core comprising a biologically inert excipient orfiller (clay like kaolin or water-soluble polymer), and a second layersurrounding the first layer comprising a mixture of a cationiccopolymeric acrylate resin and a basic compound (like calcium carbonate,aluminium hydroxide or magnesium carbonate). Additionally, it teachesthat the active ingredient can be fixed to the core by a binder materiallike polyvinylpyrolidone, methycellulose, or pharmaceutically suitablegums and that the acrylate resin for the second coating layer can bechosen from methacrylate and neutral methacrylic acid ester copolymers.This patent exemplifies a mixture of kaolin clay and povidone (polyvinylpyrrolidone) as a first layer and a mixture of calcium carbonate andEudragit E-100 copolymeric methacrylate resin as a second layer. In bothcases isopropanol and acetone are used as solvents for the preparationof the respective coating layer and allowed to evaporate after theaddition of the respective material.

WO 03/075895 A1 discloses taste masked veterinary solid compositionsconsisting of a substrate in pellet or tablet form in which fine-grainedparticles of a neutral-tasting, physiologically compatible, solidcarrier material are embedded. These fine-grained particles of carriermaterial have an average diameter of 0.09 to 0.8 mm and are coated withan active substance. This active substance layer is covered with aprotective layer of a physiologically compatible polymer matrix. Thus,the active ingredient is not present in the core but in a first layerthat is protected by a second layer. In such particles, the outer layerfulfills the same task and exerts the same disadvantages as those citedabove where the active substance is located in the core. The distinctionis that the production process is started with an inert core and thatthe active ingredient is applied to that core by a coating step.

A disadvantage of layering techniques is that a highly soluble compoundtends to dissolve at least partially in the coating solution during thecoating step, so that after drying small amounts of the substance arethen distributed also in the coating layer. In some cases this might notbe critical; however, unpleasant tasting substances are perceptible byan animal which will often refrain from taking the preparation.

The technique of multiple layering can be used for the manufacture ofparticles with more than one active ingredient. EP 2127643 A1 disclosesgranules, consisting of an inert core, coated with the (first) activeingredient, further coated with a release-regulating polymer, finallycoated with a so-called functional ingredient. Such functionalingredient can be, for example, an inhibitor of the first activeingredient thus allowing a timely regulated activity profile of thiscompound. But, the release-regulating polymer is not a polymer thatcompletely inhibits the release of the active compound but is used as adiffusion barrier leading only to time-delayed release. Such particlesdo not solve the problem discussed here.

European patent application EP 551820 A1 addresses the same problemespecially with respect to overall liquid medical formulations. Itteaches the preparation of particles that comprise an active ingredientby fluid bed granulation processes. In a second step such granules arecoated by a lacquer, also called a microencapsulation process. A largenumber of theoretically possible coating substances, esp. polymers, isdisclosed. Exemplified substances are combinations of Eudragit® NE 30 Dwith HPMC, with MC and with triethyl citrate. However, the essence ofthis development resides in the fact that the active ingredient is notused as it is, esp. not as a water soluble salt but in its least watersoluble form like the free acid or the free base. Accordingly, thisteaching does not extend to the respective salts or other water solubleforms of the pharmaceutically active ingredient.

The problem of finding an appropriate taste-masking technique is alsoaddressed by WO 2006/074185 A2, which describes dissolving or dispersinga pH dependant polymer and a so called “non-plasticizing activepharmaceutical ingredient” in a solvent which is granulated by itself(and thus forming an active ingredient containing core) or used asmaterial for forming layers over a solid support. Both approaches arethen optionally followed by applying a taste masking overcoating layer.WO 2006/074185 A2 provides that the pH dependent polymer itself servesas taste masking agent, meaning that the active compound and theprotective agent are not separated in two phases but form one phase. Dueto the physicochemical interaction between the compound and the polymerthis one phase does not dissolve but stays intact as long as the tasteperception might occur. The specification explains that useful activepharmaceutical ingredients for this technique are characterized by thefact that they are relatively non-tacky and generally will remainrelatively non-tacky so as to render coated solid supports workable whencombined with the first taste masking material whether or not up toabout 25% by weight of a conventional anti-tack agent, such as talc ormagnesium stearate is added. But, a “plasticizing” active pharmaceuticalingredient cannot meet this requirement. Accordingly this teachingcannot be generally applied to all sorts of active ingredients.

The granules (or pellets) provided by all of these techniques areusually not used per se as pharmaceutical substances but representformulation intermediates to be integrated into more complexpharmaceutical compositions. Such a composition can be e.g. in solidform (for example a tablet), or in liquid form (for example asuspension), which is another burden for the stability and/ordisintegration properties of the incorporated substance containingparticles.

The scientific publication of Wagner et al. (2000), entitled“Development of disintegrating multiple-unit tablets on a high-speedrotary tablet press”, in the European Journalof Pharmaceutics andBiopharmaceutics, volume 50, pages 285 to 291, describes the complexinterplay between composition parameters such as polymers for coating,pellet size and pellet properties, the proportion of pellets in amixture, and the type of filler-binders, and of machine parameters, suchas production rate and type of feeder. The publication discloses AvicelPH 101 to be the most suitable filler-binder for the overall tablet, andwith respect to coating elasticity and thickness, Eudragit FS 30 D isdisclosed as an advantageous coating for granules. Pellets coated withEudragit FS 30 D are taught to withstand the stress of tableting.However, they show disadvantages with respect to the disintegrationprocess of the tablet.

To date, taste masking of pharmaceutically active ingredients which arewater-soluble, especially highly water-soluble ones that also containeither at least one basic group and/or a bitter taste, is not resolved.

Due to the basic group and/or the bitter taste such compounds have to bemasked away from the smell and/or taste perception of the patient. Butthe water soluble nature of the compound regularly leads to at leasttraces of the compound diffused within the particle and/or the coatingslayers already during the coating process itself, i.e. before therespective coating layer has dried, just because the compound isdissolved at least partially by the solvent of the respective coatinglayer material during the coating process. Accordingly, whereas the mainportion of the compound might be hidden away by the established coatingtechniques, traces of it may be perceptible. Such perception by thepatient, especially animals, may result in the patent refraining fromtaking the medicament or composition.

For example, published application US 2005/287211 A1 discloses particlescomprising a core of microcrystalline cellulose spheres coated by thethree layers: a substance layer, a middle layer and an outer coatinglayer. Middle layers of the disclosed examples comprise povidone orhydroxypropylmethylcellulose (HPMC) as sole polymers. The disclosedouter coating layers comprise e.g. a mixture of HPMC and ethylcelluloseor a poly(meth)acrylate. However, all exemplified middle layersadditionally comprise a strongly water soluble ionic compound, in mostcases NaH₂PO₄, Na₂HPO₄, Na₂CO₃ or citrate. This strongly water solubleionic compound influences the physicochemical properties of the coatingsnot only during the dissolution of the particle (as addressed by therespective publication) but also during the production of the particle,which leads to perceptible amounts of the active ingredient by thepatient/animal.

WO 2009/011967 A1 discloses particles that comprise a core of sucrosecoated by the layers of a substance layer (a non-steroidalanti-inflammatory drug), a first protective layer comprising HPMC or amixture of HPMC and polyethlenglycol (PEG), an optional enteric coatinglayer or intermediate coating layer (a methacrylate/acrylate-polymerwith triethylcitrate) and an optional second protective layer comprisingHPMC again (e.g. a mixture of HPMC and PEG). Additionally, one of thecoating layers comprises a strongly water soluble ionic compound. Tasteand taste masking are not addressed or considered in WO 2009/011967 A1.

WO 2010/007515 A2 discloses particles comprising an active substancecontaining core, protected by an inner layer (polymers which swell ordissolve in the GI tract, e.g. a mixture of HPMC and PEG), anintermediate layer with a specific physiological activity (aprotease-inhibitor and/or absorption enhancer, embedded in PEG as abinding polymer), an outer layer (polymers which swell or dissolve inthe GI tract like the ones for the inner layer), and optionally, afurther outer layer with a gastro-resistant polymer(methacryl-copolymers or cellulose acetate-phthalate). These particlesare optimized, especially by the application of a protease-inhibitorand/or absorption enhancer and the selection of polymers, to resistuntimely dissolution in the GI tract and to provide a programmablerelease of the active ingredient(s). The aspect of influencing thedissolution process and/or the activity of the drug substance by theaddition of specifically acting proteins is not addressed by WO2010/007515 A2.

WO 2008/075372 A1 discloses particles comprising a core of a starchcontaining sugar sphere, covered by a seal coat, then a substance layer(drug and HPMC) as a second coat and an outer layer comprising a mixtureof the material Surelease® (ethylcellulose admixed with coconut oil)mixed in a ratio of 6:1 (w/w) with HPMC. But, these particles do notcomprise a further protective layer. It was also found disadvantageousto store the active substance in a middle layer and not in the lowestpossible layer. This structure affects the dissolution profile, as wellas, the production process.

Finally, the particles of WO 2008/027993 A2 are composed of an inertcore, an amorphous layer containing the drug (with a crystallizationinhibiting polymer, also named solubility-enhancing polymer, and asolubility enhancing organic acid), a protective seal-coating layer(povidone) and finally a “lag-time coating” (TPR coating;water-insoluble polymer and an enteric polymer). All examples discloseouter coatings with the plasticizers diethylphthalate ortriethylcitrate. So, this specific architecture aims at a sustainedrelease following lag-time but is not optimized with respect to theproduction of the particle.

Accordingly, there is a need in the art to optimize the palatability ofpharmaceutical compositions, especially for use in veterinary medicineby masking the taste of a pharmaceutically active compound which iswater-soluble, especially a highly water-soluble active compound thatalso comprises either at least one basic group and/or a bitter taste.Such compositions should at the same time allow the release of theingredient in the patient's body as soon as necessary.

Exemplary preferred pharmaceutical compositions include thepharmaceutically active ingredients of DPP IV-inhibitors, i_(f)-channelblockers, phosphodiesterase III inhibitors, cyclooxygenase 2 inhibitors,and benzodiazepine receptor agonist.

Ideally, a masking technique would allow acceptable formulationintermediates to be incorporated into oral dosage forms forpharmaceutical compositions, especially in the field of veterinarymedicine in the case of an unpleasant taste of the active ingredient.Such a masking technique should be applicable to a substance containingparticles that contain the active ingredient(s) in the inner core, aswell as, to granules that provide the active ingredient in the form of acoating layer over an inert or already sub-coated core, the layer(s)beneath and/or the core optionally comprising other active ingredients.

A desired masking technique should be especially useful for thosepharmaceutically active ingredients that are highly soluble in waterand/or in other solvents that are used for coating layers. Ideally, thedesired masking technique should be applicable to solid and non-solid,especially liquid, formulations with only minor variations. The dosageform should also allow subdividing into pieces or volumetric dispensingin order to adapt the dose, without destroying the taste masking of thepharmaceutically active ingredient.

Preferably, the desired masking technique is highly flexible withrespect to the amount of the pharmaceutically active ingredient to beincorporated into the pharmaceutical composition; cost effective; andeasy to apply in a standard manufacturing apparatus.

SUMMARY OF THE INVENTION

This problem is solved by the invention of a taste masked multi-layeredparticle comprising a pharmaceutically active ingredient, comprising:

-   a) an inert core,-   b) one or more coating layer(s) comprising the pharmaceutically    active ingredient and a binder,-   c) an intermediate coating layer (seal coating) free from a low    molecular weight water -soluble ionic compound, comprising a    water-soluble pharmaceutical film-forming compound, selected from    -   (i) hydroxypropyl methylcellulose (HPMC) and polyethylene glycol        (PEG) or    -   (ii) poly(1-vinylpyrrolidin-2-one) (PVP); and-   d) an outer coating layer (final or taste masking coating) free from    a low molecular weight water-soluble ionic compound, comprising    -   (i) a poly(meth)acrylate or    -   (ii) a mixture comprising 60-90% (w/w) ethylcellulose (EC) and        10-40% (w/w) hydroxypropyl methylcellulose (HPMC),        wherein the pharmaceutically active ingredient is water-soluble        and comprises either at least one basic group and/or a bitter        taste.

In other words: The solution of the above mentioned problems consists inwell-assembled coated drug loaded subunits (multi-layered particles orpellets). According to the invention they can be produced starting frominert particles (or spherical carriers or pellets) that are coatedstepwise by specific layers. For this purpose they are first layeredonce or more than once with a layer comprising a specificpharmaceutically active ingredient; the drug layer is then covered by anintermediate coating layer (seal coating) and then by an outer coatinglayer (final or taste masking coating).

A second aspect of the present invention provides methods for theproduction of such multi-layered particles.

A further aspect of the present invention provides the use of certaincompounds or mixtures of compounds for the assembly of intermediatecoating layers (seal coating) or of outer coating layers (final or tastemasking coating) of such multi-layered particles.

Further aspects of the present invention provide uses of themulti-layered particles according to the invention as well aspharmaceutical uses and pharmaceutical compositions comprising them.

These and other aspects of the present invention are described herein byreference to the following figures and examples. The figures andexamples serve for demonstrative purposes and do not limit the scope ofthe claims.

As explained below in more detail and demonstrated by the examples ofthis application, the multi-layered particles according to the inventionare taste masked and at the same time they show advantageous dissolutionprofiles. Especially the exemplified material basic butylatedmethacrylate copolymer turned out to be an extremely good outer coatinglayer which is insoluble in neutral pH environments (meal and mouth ofthe patient), but dissolves quickly at acidic pH (stomach), therebyallowing the particle to disintegrate and to release the drug. Theyfurther provide an acceptable mouth-feeling, i.e. no grittiness for thepatient.

Accordingly, the multi-layered architecture of the particles of theinvention allows the formulation of palatable pharmaceuticalcompositions, especially for use in veterinary medicine, even withpharmaceutically active ingredients that would otherwise be rejected bytaste-sensitive patients. Thus the acceptance and compliance ofrespective pharmaceutical composition is ameliorated.

The features, esp. the mechanical stability of the multi-layeredparticles according to the invention further allow versatilepharmaceutical compositions with the possibility for accurate doseadjustment, in solid as well as in overall liquid or pasteous form.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1: Dissolution curves at pH 1 (FIG. 1A) and pH 6.8 (FIG. 1B) frommulti-layered particle prototypes coated with basic butylatedmethacrylate copolymer, produced according to Example 1, at differentcoating levels (aqueous process). (Means±SD, n≧3, are shown).

FIG. 2: Dissolution curves at pH 1 (FIG. 2A) and pH 6.8 (FIG. 2B) frommulti-layered particle prototypes coated with basic butylatedmethacrylate copolymer, produced according to Example 1, at differentcoating levels (organic solvent process). (Means±SD, n≧3, are shown).

FIG. 3: Dissolution curves at pH 1 and pH 6.8 of active ingredient frommulti-layered particles with 200% poly(meth)acrylate aqueous coating(FIG. 3A) and from the derived tablets (FIG. 3B) produced according toExample 1. (Means±SD, n≧3, are shown).

FIG. 4: Dissolution curves at pH 1 and pH 6.8 from multi-layeredparticle prototypes coated with EC/HPMC 70:30, according to Example 2.(Means±SD, n≧3, are shown).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The invention provides taste masked multi-layered particles.

Herein and in the appended claims, the singular forms “a”, “an”, and“the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a preparation” includes aplurality of such preparations. Unless defined otherwise, all technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of skill in the art to which this invention belongs atthe time of filing. The meaning and scope of terms should be clear;however, in the event of any latent ambiguity, definitions providedherein take precedent over any dictionary or extrinsic definition.Herein, the use of “or” means “and/or” unless stated otherwise.Furthermore, the use of the term “including”, as well as other formssuch as “includes” and “included” is not limiting. All given ranges andvalues may vary by 1 to 5% unless indicated otherwise or known otherwiseby the person skilled in the art, therefore, the term “about” wasomitted from the description. Although any methods and materials similaror equivalent to those described herein can be used in the practice ortesting of the present invention, the preferred methods, devices, andmaterials are now described.

“Particles”, according to the invention, are overall solid piecesproduced for example by the processes described below; the word “Pellet”can be used synonymously for “particle”. They are regularly used asformulation intermediates esp. for pharmaceutical compositions, meaningthat they provide the pharmaceutically active ingredient in a form thatcan be incorporated in finally composed pharmaceutical compositions.These can be overall solid preparations of material, e.g. solidpharmaceutical compositions; alternatively, the particles according tothe invention can make up the solid phase of a suspension in an overallnon-solid, e.g. pasteous or especially liquid composition, esp. apharmaceutical liquid composition.

The particles according to the invention are “multi-layered” which meansthat they are characterized by a well-designed architecture in whichinert particles (or spherical carriers or pellets) are coated by one ormore layers comprising a specific pharmaceutically active ingredient, ontop of this by an intermediate coating layer (seal coating) and then byan outer coating layer (final or taste masking coating). Details of thisarchitecture as well as materials that can be used for it are explainedbelow.

“Taste masked”, in the sense of the invention, means that molecules withan unpleasant taste are hidden away from the patient's perception, notonly covered with another, more pleasant taste or flavor. “Taste masked”according to the invention is to be understood as a functional term,especially with respect to the natural taste perception of a human or ananimal. The task of masking the taste of a pharmaceutically activeingredient is regarded to be solved as soon as a statisticallysignificant number (more than 60%, preferably more than 70%, even morepreferred more than 80%, most preferred more than 90% or even more than95%) of the addressed patient population does not refrain from voluntaryingestion of a pharmaceutical composition comprising the respectivetaste masked multi-layered particles in comparison to a pharmaceuticalcomposition comprising a less efficiently masked or non-maskedpreparation of the same pharmaceutically active ingredient in an overallcomparable pharmaceutical composition.

The taste masked multi-layered particles according to the invention canbe used for pharmaceutical compositions for the medical treatment ofhumans as well as for the medical treatment of animals. Such medicaltreatment means all kinds of treatments that can be exerted by oraladministration of a pharmaceutically active compound, includingprophylaxis, immunization and therapy.

The multi-layered particles according to the invention are especiallysuitable and intended for use in veterinary medicine. This feature ofthe invention is not to be understood as a restriction of the patientpopulation to animals only. It is to be understood as a quality feature.Animals like e.g. cats are characterized by an extremely good perceptionof taste in comparison to humans, and the examples provided with thisapplication show that the preferred solutions do solve the problem evenwith respect to cats as addressed patient population. Multi-layeredparticles are especially covered by the invention, when the masking ofthe taste is so efficient that even taste sensitive animals like cats ordogs as patient population specifically addressed by the derived, fullyformulated pharmaceutical composition (at the mentioned predefinedpercentage) do not refrain from the voluntary ingestion of the derived,fully formulated pharmaceutical composition.

The use of multi-layered particles according to the invention for use inveterinary medicine is preferred because the need for taste masking ofpharmaceutically active ingredients is especially persistent in thistechnical area. This is especially true in the context of the compoundgroups described in more detail below that are specifically addressed bythe invention.

“Pharmaceutically active ingredients”, in the sense of the invention,are per se all kinds of chemical or biological substances useful for theprophylaxis, immunization or therapy of a disease of an animal or ahuman patient. The pharmaceutically active ingredient is regularlyincorporated in its chemical form most appropriate for the medicaltreatment, e.g. as solvate, salt or ester. Preferred examples ofpharmaceutically active ingredients will be explained below.

Form a chemical point of view, the pharmaceutically active ingredientsrelevant for the invention are “water-soluble and comprise either atleast one basic group and/or a bitter taste”.

As explained above, the invention had to be made with respect to suchcompounds that have a high tendency to (i) be perceived by the patientsand (ii) to dissolve in the coating material during the storage of theparticles and/or the derived formulation and/or in the solution of thecoating material during the production of the particles. As exemplified,the coatings according to the invention allow such a highlysophisticated taste masking.

Water-solubility is in most cases due to polar groups as part of thecompound allowing water molecules to assemble respectively and to buildup a hydration shell. Most preferred are ionic compounds whichquantitatively dissolve in at least one anion and at least one cationduring the solvation in water.

Preferred are compounds with a bitter taste because especially thistaste has to be masked and can be masked by the teaching of theinvention. For example several N-containing groups are polar or evencationic and at the same time responsible for a bitter taste.

The essence of the invention resides in the unique architecture of themulti-layered particles, comprising an inert core and the coating layersdescribed in the following.

The “inert core” according to the invention is a particle (or sphericalcarrier or pellet). It has been found advantageous to use particles witha diameter of about 50 to 300 μm, preferably with a small degree ofvariation. Preferred sub-ranges are defined below.

The material used for the inert core is chemically inert, in the sensethat it does not react with any of the other ingredients of themulti-layered particle according to the invention and especially doesnot interfere with the intended pharmacological mechanism exerted by thepharmaceutically active ingredient of the multi-layered particle.Examples for a material used for the inert core are cellulose, esp.microcrystalline cellulose, starch, lactose, sugar, mannitol or mixturesthereof.

The coating process as described below regularly starts with thematerial for the inert cores. According to the invention it is intendedthat each single particle of this starting material serves as a singlecore for each multi-layered particle according to the invention. Theprocess is a statistical process with Gauss' distribution curves for theresults of each step. This leads to statistical results, meaning thateach layer has got an average thickness. It is preferred thatmulti-layered particles with more than only one single inert coreparticle be sieved off and in doing so be excluded from incorporationinto a pharmaceutical composition.

The methods for the coating process, i.e. for the subsequent addition oflayers onto a smaller particle are per se known to the person skilled inthe art. Such are described for example in the textbook “DevelopingSolid Oral Dosage Forms—Pharmaceutical Theory and Practice”, chapter 34,edited by Yihong Qiu, Yisheng Chen and Geoff G. Z. Zhang; Elsevier(2009).

Also the apparatus for granulation processes are known to the personskilled in the art, for example “Developing Solid Oral DosageForms—Pharmaceutical Theory and Practice”, chapter 34, edited by YihongQiu, Yisheng Chen and Geoff G. Z. Zhang; Elsevier (2009).

The “one or more coating layer(s) comprising the pharmaceutically activeingredient and a binder” which, according to the invention, is layeredonto the core particle, contains the pharmaceutically active ingredient,regularly in its chemical form appropriate for the medical treatment. Itfurther contains a binder and optionally other ingredients that as amixture are intended to form the respective coating layer.

Useful binder materials include but are not limited to tragacanth,gelatin, starch, cellulose materials such as methyl cellulose,microcrystalline cellulose and sodium carboxy methyl cellulose, alginicacids and salts thereof, polyethylene glycol, PVP, guar gum,polysaccharide acids, sugars, invert sugars and the like. Preferred arehydroxypropyl methylcellulose (HPMC) and/or polyvinylpyrrolidone (PVP).

The material HPMC (also called Hypromellose; the name HPMC according toDIN EN ISO 1043-1: 2002-06, E 464) is a mixed ether of cellulose with2-hydroxypropyl and methyl groups. Technically it is usually prepared bythe reaction of cellulose with methylchloride and propylene oxide. Itcan be purchased commercially, e.g. by the supplier Harke Pharma underthe trade name Pharmacoat®.

The material PVP (also called Poly(1-vinylpyrrolidin-2-one) orPolyvidon; the name PVP according to DIN EN ISO 1043-1: 2002-06) is avinylpolymer of the general structural formula:

and with molecular weights between 2,500 and 750,000 g/mol, which againdepends on the degree of polymerization. They are characterized by Kvalues which are calculated from the viscosity of 1% or 5% aqueoussolution. PVPs are technically usually prepared by radicalpolymerization of 1-vinylpyrrolidin-2-one.

Binders may be used in an amount of up to 60% (w/w). It has been foundadvantageous that the drug layer on the pellets consists of up to 40%(w/w), preferably 5 to 20% (w/w) of binder. More preferred ranges aredefined below. In another preferred aspect according to the inventionthe drug layer on the pellets consists of 1-30% (w/w) of the binder.

The coating material for this layer can advantageously be applied in theform of a liquid solution or suspension of the binder material in waterwhich is allowed to evaporate after the addition of the material.

While using the fluid bed coating process, it is preferred to spray theliquid mixture onto the core particles. It is preferred that the coatinglayer comprising the pharmaceutically active ingredient and a binder isadded up to a thickness of more than 20 μm, and increasingly preferredmore than 30, 40, 50, 60, 70, 80 and 100 μm and mostly preferred between50 and 100 μm. Such variability allows adding the pharmaceuticallyactive ingredient to an extent that is appropriate to reach the desiredconcentration of active ingredient in the finally preparedpharmaceutical composition.

This coating step can be repeated in order to allow the addition of asecond coating layer(s) comprising the pharmaceutically activeingredient. The material for this optional second layer can be identicalwith the first one. However, variations of this composition in order tooptimize physicochemical parameters also lie well within the ambit ofthe invention. The second layer can be added to the same or to adifferent thickness than the first layer. In doing so a double coatinglayer comprising the pharmaceutically active ingredient of more than 200μm in total is possible. Example 1 of this specification shows theproduction of a particle comprising two layers each comprising thepharmaceutically active ingredient and a binder with a thickness ofabout 140 μm in total.

The “intermediate coating layer (seal coating) comprising awater-soluble pharmaceutical film-forming compound” is to be understoodas a complete coating layer around/on top of the layer comprising thepharmaceutically active ingredient serving especially two purposes: (i)mechanical stability for the particle as a whole and especially for theintegrity of the layer comprising the pharmaceutically activeingredient, and (ii) barrier against the dissolution of thepharmaceutically active ingredient within the particle, especiallyduring the production of the particle as well as during the storageperiod of the complete multi-layered particles and the fully formulatedpharmaceutical composition. Besides the water-soluble pharmaceuticalfilm-forming compound, further ingredients can optionally be present inthis coating layer.

According to the invention, this coating layer is layered onto the oneor more coating layer(s) comprising the pharmaceutically activeingredient and a binder. It has been found advantageous to apply thiscoating layer by way of suspension or solution in water or an organicsolvent, also mixtures of water and e.g. ethanol are possible.

Appropriate water-soluble film-forming compounds are those that qualifyas pharmaceutically acceptable chemical compounds. From a chemicalperspective they can be described as hydrophilic polymers or mixturesthereof. According to the invention, such a water -solublepharmaceutical film-forming compound is especially selected from (i) amixture of hydroxypropyl methylcellulose (HPMC) and polyethylene glycol(PEG) or (ii) poly(1-vinylpyrrolidin-2-one) (PVP). According to anotheraspect of the invention the water-soluble pharmaceutical film-formingcompound is selected from for example HPMC, PVP, methyl cellulose,hydroxy ethyl methyl cellulose, hydroxy ethyl cellulose or sodiumcarboxymethyl cellulose or mixture of one or more of these compounds.

The material hydroxypropyl methylcellulose (HPMC) has already beendiscussed above.

The material polyethylene glycol (PEG) makes up a large group ofpolyethers with the general structural formula:H—[—O—CH₂—CH₂—]_(n)—OHand with molecular weights between 200 and 5,000,000 g/mol, whichdepends on the degree of polymerization. Technically they are usuallyprepared by anionic polymerization of oxiran (ethyleneoxid) orpolycondensation of 2-chloroethanol (ethylene chlorohydrin). Dependingon the chain length, they comprise a liquid to waxy overall appearance.They dissolve in water and several organic solvents. According to theinvention it is preferred to use a PEG with a molecular weight between4,000 and 8,000 preferably around 6,000 g/mol which are usually calledPEG 4000, PEG 8000 and PEG 6000 and the like, the name depending on themolecular weight. Such PEG can be purchased commercially, e.g. by thesupplier Dow Chemicals, Schwalbach, Germany, under the trade nameCarbowax Sentry®.

In a preferred mode of the invention the material for this coating layeradditionally comprises talc and/or magnesium stearate. In another aspectof the invention this coating additionally layer comprises one or moreof the following anti-tacking agents such as talc, magnesium stearate,calcium docosanoate, stearic acid, calcium arachinate, hydrogenatedcastor oil, or triglycerides.

The mixture for this coating layer can advantageously be added to therespective particles in the form of an aqueous solution or suspension.Employing an aqueous process is especially advantageous with respect tocost, work safety and environmental reasons.

The material poly(1-vinylpyrrolidin-2-one) (PVP) has already beenpresented above.

According to the invention it is preferred to add PVP and optionallytalc in the form of a solution in an organic solvent like ethanol and/oraceton.

The thickness of the seal coating layer (c) can vary with respect to thespecific particle. Preferably, it lies between 5 and 40% (w/w) of thedrug layered particles, more preferred between 10 and 30% (w/w) evenmore preferred between 15 and 25% (w/w).

The ideal thickness in each case can be developed experimentally by aperson skilled in the art, with respect to the following considerations:The seal coating serves as protective coating to mechanically stabilizethe complete particle and the pharmaceutically active ingredientcontaining layer for the following coating steps and to preventmigration of the drug active ingredient into the outer layer when thefinal coating is applied or even during storage (see above). The sealcoating is deemed to be thick enough when no (or only traces of) thecompound can be detected on the outer surface of the particles. Anappropriate detection method is Energy Dispersive X-ray analysis (EDS).The final decision, however, is based on the statistical analysis of thederived, fully formulated pharmaceutical composition with the envisagedtaste sensitive patient population, as explained above.

The “outer coating layer (final or taste masking coating) comprising (i)a poly(meth)acrylate or (ii) a mixture comprising 60-90% (w/w)ethylcellulose (EC) and 10-40% (w/w) HPMC” is a complete coating layeraround/on top of the intermediate coating layer (seal coating). Withoutwishing to be bound by this theory, it is believed that especially thiscoating is responsible for the taste masking properties of themulti-layered particles according to the invention, esp. by inhibitingthe diffusion of the pharmaceutically active ingredient to the surfaceof the particle, neither during production nor during the storage of theparticles and/or the derived pharmaceutical compositions. It furtherserves the purpose of mechanical stabilization of the particle as awhole and especially for the integrity of the layers underneath.

The material poly(meth)acrylate appropriate for the invention is apolymer derived from the polymerisation of esters of acrylic andmethacrylic acid.

The state of the art discloses a broad range of chemical derivatives ofsuch a polymer, derived by the addition of certain side chains (R) tothe backbone, i.e. by the polymerization with different methacrylic acidesters, e.g. with neutral ester groups (—COOCH₃ or —COOC₄H₉), anionicgroups (—COOH), cationic groups (—COOCH₂CH₂N(CH₃)₂) and neutral ionicgroups (—COOCH₂CH₂N⁺ (CH₃)₃Cl⁻).

The use of poly(meth)acrylates with neutral or cationic groups ispreferred.

This material can be purchased in different physical forms like aqueousdispersion, organic solution, granules or powders. With respect to themode of application it is preferred to use a powder or a solution thatfits to the solvent to be used for the respective coating process,respectively.

Further physico-chemical properties of this material can be found in theliterature, e.g. in the Eudragit® Application Guidelines, Evonik RöhmGmbH, Business Line Pharma Polymers, Darmstadt, Germany, which companyis also one commercial supplier of this material.

The representatives of this material which are useful for the invention,are characterized by their specific solubility profile that depends onthe pH value of the surrounding medium and is preferably insoluble inneutral pH environments but soluble at acidic pH values. Such usefulrepresentatives are for example:

-   -   A cationic copolymer based on dimethylaminoethyl methacrylate,        butyl methacrylate, and methyl methacrylate with a ratio of        2:1:1, preferably with a molecular weight between 40,000 and        50,000, more preferred about 47,000 g/mol (or basic butylated        methacrylate copolymer, as disclosed in European Pharmacopoeia        or the INCI name dimethylaminoethyl methacrylate copolymer, or        the IUPAC name poly(butyl methacylate-co-(2-dimethyl-aminoethyl)        methacrylate-co-methyl methacrylate) 1:2:1); commercially        available e.g. under the trade name Eudragit® E, or Eudragit® E        PO in its powder form, from Evonik Röhm GmbH, Business Line        Pharma Polymers, Darmstadt, Germany.    -   A copolymer of ethyl acrylate, methyl methacrylate and a low        content of a methacrylic acid ester with quaternary ammonium        groups (trimethylammonioethyl methacrylate chloride) with a        ratio of approx. 1:2:0.1, preferably with a molecular weight        between 30,000 and 40,000, more preferred about 32,000 g/mol (or        Ammonio Methacrylate Copolymer, Type B, as disclosed in European        Pharmacopoeia); commercially available e.g. under the trade name        Eudragit® RS, or Eudragit® RS PO in its powder form, from Evonik        Röhm GmbH.    -   A copolymer of ethyl acrylate, methyl methacrylate and a low        content of a methacrylic acid ester with quaternary ammonium        groups (trimethylammonioethyl methacrylate chloride) with a        ratio of approx. 1:2:0.2, preferably with a molecular weight        between 30,000 and 40,000, more preferred about 32,000 g/mol (or        Ammonio Methacrylate Copolymer, Type A, as disclosed in European        Pharmacopoeia); commercially available e.g. under the trade name        Eudragit® RL, or Eudragit® RL PO in its powder form, from Evonik        Röhm GmbH.    -   A neutral copolymer based on ethyl acrylate and methyl        methacrylate, ratio approx. 2:1, preferably with a molecular        weight of at least 500,000, more preferred between 700,000 and        800,000, most preferred about 750,000 g/mol (or Polyacrylate        Dispersion 30 Per Cent, as disclosed in European Pharmacopoeia);        commercially available e.g. under the trade name Eudragit® NE in        30% dispersion from Evonik Röhm GmbH.

In one mode of the invention the poly(meth)acrylate component is blendedwith magnesium stearate which is especially useful when an organicsolvent process is used for the application of this coating onto therespective particles. Without wishing to be bound by this theory, it canbe assumed that these two compounds in this combination fulfill thesefunctions: poly(meth)acrylate acts as functional coating, allowingespecially a pH dependent disintegration of the particle (stable inneutral pH, disintegrating in acidic pH); magnesium stearate functionsas anti-tacking agent. Talc and/or colloidal silica can optionally beadded to counteract electrostatic charging. In another aspect of theinvention other anti-tacking agents are for example talc, magnesiumstearate, calcium docosanoate, stearic acid, calcium arachinate,hydrogenated castor oil, or triglycerides.

In an alternative approach the poly(meth)acrylate coating can be appliedby an aqueous process. In this case it is preferred to form a totalmixture comprising sodium lauryl sulfate (as wetting and dispersingagent), stearic acid (as salt former and further for forming a colloidalsolution with poly(meth)acrylate) and/or magnesium stearate (asanti-tacking agent). Alternative anti-tacking agents are for exampletalc and/or silica. Again, the given functions of these additionalcomponents are based on the best knowledge up to date but cannot bebinding with respect to the disclosure of the invention. Talc and/orcolloidal silica can optionally further be added to counteractelectrostatic charging.

Alternatively, a mixture comprising 60-90% (w/w) ethylcellulose (EC) and10-40% (w/w) HPMC can be used as material for the outer coating layer.

The material ethylcellulose (EC; the name according to DIN EN ISO1043-1: 2002-06) is the ether of cellulose with ethyl groups.Technically it is usually prepared by the reaction of alkalicellulosewith ethylchloride, which can lead to types of EC differing with respectto the degree of substitution. Ethylcelluloses with substitution degreesbetween about 1.1 and 1.4 are soluble in water; those with higherdegrees of substitution are soluble in organic solvents. Commerciallyavailable EC types with substitution degrees between about 2.2 and 2.6are thermoplastic with a softening point between around 150 and 160° C.Commercially available EC types are offered with different molecularweights which further influence the physico-chemical properties of thematerial like their viscosity.

According to the invention it is preferred to use EC with a substitutiondegree between 2.2 and 2.6 and/or with a degree of polymerizationresulting in a viscosity of 41-49 mPa·s (measured as 5% solution in 80%toluene and 20% ethanol). Such EC can be purchased commercially, e.g. bythe supplier Dow Chemical under the trade name Ethocel® Std. 45.

The material HPMC has already been presented above.

According to the invention, the ratio of HPMC and EC can be varied inthe given frame in order to achieve the desired release profile, esp.with respect to the following considerations. Without wishing to bebound by this theory it is assumed that in a blend of EC and HPMCaccording to the invention, the HPMC dissolves firstly after ingestionby the patient and thus leaves pores in the EC film. Then water canpenetrate through the pores into the core of the pellets and therebyallow the pharmaceutically active ingredient to be released with a lagtime, i.e. the time the HPMC needs to be washed out of the film. TheEC/HPMC film composition and the coating thickness (see below) can beoptimized in a way to generate a lag time that is considered long enoughto allow the dosage form to be ingested without the drug being released.

For both alternatives, the poly(meth)acrylate and the EC/HPMC films, thecoating thickness and the way the coating is applied to the pellets canbe varied/optimized in order to achieve the desired drug release profileor make the process feasible, i.e. aqueous vs. organic solvent sprayingprocess. Such variations lie well within the reach of a person skilledin the art. Preferred values are disclosed in more detail below.

Moreover, the final coating layer may advantageously comprise furthersubstances. For example magnesium stearate is used to counteractelectrostatic charging during processing. Another example issiliciumdioxide to reduce electrostatic charging of the product. Furtherexamples are talc, magnesium stearate, calcium docosanoate, stearicacid, calcium arachinate, hydrogenated castor oil, or triglycerides.

Both, the intermediate coating layer (seal coating) (c) and the outercoating layer (final or taste masking coating) (d) are furthercharacterized by the feature “free from a low molecular weightwater-soluble ionic compound”.

Without wishing to be bound by this theory, this feature has been foundto be one important reason for the efficiency of the taste-masking ofthe particle as well as of the derived pharmaceutical compositions andthus the usefulness of the invention. Whereas the state of the artteaches that compounds like NaH₂PO₄, Na₂HPO₄, Na₂CO₃ or citrates,especially the salts of strong acids with strong bases, are useful asdissolution aids of the particles and thus helpful for the applicationof the pharmaceutical ingredient to the patient's body. However, in thecontext of the taste-masking of a pharmaceutically active ingredientwhich is water-soluble and comprises either at least one basic groupand/or a bitter taste, it was found to be advantageous to avoid suchcompounds.

However, less ionic compounds like talc, stearic acid, sodium laurylsulfate or magnesium staerate, especially oxides or the salts of weakacids used e.g. as lubricants, coloring agents and/or anti-tackingagents and the like are found to be not so critical for thetaste-masking effect and are thus allowed as optional ingredients. Thisaspect will be explained in more detail below.

The selection of such additional compounds in the layers (c) and (d) isthus limited by their ability to dissolve in water. They are uncriticaland therefore not water-soluble ionic compounds in the sense of theapplication as long as 1 g of such a compound is completely dissolved bynot less than 100 ml water, at a temperature of 25° C. and 1013.25 hPaatmospheric pressure. Increasingly preferred they possess solubilityvalues of at least 250, 500, 750, 1000, 2000, 3000, 4000, 5000, 6000,7000, 8000, 9000, 10000, 15000 and more than 20000 ml water for thetotal dissolution of 1 g of the respective substance under the sameconditions.

Compounds with low molecular weight, according to the invention, aredefined as those with a molecular weight below 750 Da, increasinglypreferred below 700, 600, 500, 400, 300, 200 and 150 Da.

The different coating materials are preferably applied to the respectiveparticles in the form of a liquid solution or suspension in anappropriate solvent. This solvent can be selected from (purified) wateror organic solvents.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention described above, wherein thepharmaceutically active ingredient is selected from one or more of thefollowing compound groups:

α) a DPP IV inhibitor,

β) an i_(f)-channel blocker,

γ) a phosphodiesterase III inhibitor,

δ) a cyclooxygenase 2 inhibitor and/or

ε) a benzodiazepine receptor agonist.

These compound groups are a priori not defined by their chemicalclasses, but they are defined by their high specificity for one or(theoretically) more than one of these five specific targets, whichspecificity is high enough to allow a medical therapy based on theinteraction of these compounds with their specifically bound targets.The binding characteristics of the compounds to their specific targetsreside in interactions of the compounds with the three dimensionalstructure of the addressed region of the target protein, mainly based onionic interactions, hydrogen bonds, Van-der-Waals bonds and/orhydrophilic/hydrophobic interactions in general. Accordingly, allcompounds within one of these groups are to be seen as a group withsimilar stereochemistry and a similar architecture ofhydrophilic/hydrophobic, ionic etc. groups placed on the scaffold of thecompound.

This correlates with the fact that the invention has proven to beespecially useful for pharmaceutically active ingredients that tend todissolve and/or to diffuse in water or any other solvent, especially ina solvent that is used for the addition of coating materials ontorespective particles.

Among these substances, the invention is useful for those with anunpleasant, e.g. bitter taste. Such a taste is regularly due to specificionic groups on the respective compound, which in the other hand arenecessary for the specific interaction with the target to exert themedical effect.

“DPP IV inhibitors” according to the invention are those chemicalcompounds that interact with and inhibit the enzyme dipeptidyl peptidaseIV (DPP IV). It is believed that the inhibition of DPP IV decreases theGLP-1 proteolysis and thus prolongs the half-life of endogenousfull-length (active) GLP-1 and in doing so leads to increased plasmalevels of glucagon like peptide 1 (GLP-1). As a consequence, GLP-1induces the secretion of insulin from pancreatic β-cells in a glucosedependent manner. A reduction of glucagon levels as well as anenhancement of long-term pancreatic β-cell function in vivo arepotentially additional beneficial features of GLP-1 elevation.Especially the enhancement of long-term pancreatic β-cell function canbe characterized as a disease modifying effect; GLP-1 agonism preservesβ-cell mass by increased proliferation and decreased apoptosis whicheffects can be characterized as a β-cell regeneration effect. Furthereffects of GLP-1 elevation according to the invention include slowing ofgastric motility and induction of satiety.

In conclusion, DPP IV inhibitors can be used for the therapy ofmetabolic disorders or metabolic diseases like ketoacidosis,pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance,obesity, hyperglycemia, hyperinsulinemia, elevated blood levels of fattyacids, hyperlipidemia and/or elevated blood levels of glycerol, SyndromeX (metabolic syndrome), atherosclerosis, inflammation of the pancreasand/or inflammation of adipose tissue, especially the treatment ofdiabetes mellitus type 1 or type 2, even more preferred diabetesmellitus type 2.

Useful compounds are disclosed in WO 2005/085246 A1, especially in thederived Patent EP 1758905 B1.

The experimental part of the application comprises one example of acompound for the treatment of a metabolic disease, esp. of diabetes type2 by a bitter tasting DPP IV inhibitor from the xanthine class, i.e. by1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride, which is especially preferred in this context.

Such multi-layered particles can be used for the treatment of metabolicdisorders, esp. of diabetes type 2, e.g. by incorporation into arespective medical formulation.

“i_(f)-channel blockers” according to the invention are those chemicalcompounds that interact with and inhibit the i_(f)-channel. They arebelieved to be useful for treating and even inducing the regression ofmyocardial diseases associated with hypertrophy, in particular fortreating ideopathic hypertrophic cardiomyopathies (HCM) in humans anddomestic animals.

Useful compounds are disclosed by EP 065229 B1, especially zatebradine(see below), and U.S. Pat. No. 3,708,485, especially alinidine (seebelow).

Very useful and preferred compounds are disclosed in EP 224794 B1, amongwhich there is the preferred i_(f)-channel blocker is(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onwhich is also useful for the treatment or prevention of heart failure.It has been given the international nonproprietary name (INN)cilobradine. The hydrochloride form is called cilobradine hydrochloride.

The experimental part of the application comprises one example for thetaste masking of a compound for the treatment of heart disease from thiscompound group; this is one representative of the chemical class ofcyclic amine derivatives, i.e. of bitter tasting cilobradine (or of therespective hydrochloride form). Especially in this taste masked form itcan be used for human and for animal therapy, e.g. by incorporation intoa respective medical formulation for the treatment of heart diseases.

“Phosphodiesterase III inhibitors” according to the invention are thosechemical compounds that interact with and inhibit the enzymephosphodiesterase III (PDE 3). Without wishing to be bound by thistheory, the inhibition of PDE 3 is thought to cause peripheralvasodilation which results in decreased pressure, translating intosmaller cardiac preload and afterload and thus decreases the failingheart's workload.

Useful compounds are disclosed by WO 2005/084647 A1 and especially thederived patent EP 008391 B1.

One prominent example of such compounds is(RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one,also known under the INN pimobendan and described e.g. in EP 008391 B1and WO 2005/084647 A1. Pimobendan is known and usable as cardiotonic,hypotensive and anti-thrombotic compound and also functions as apositive inotrope which sensitizes and increases the binding efficiencyof cardiac myofibril to the calcium ions that are already presentwithout increasing the consumption of oxygen and energy. According tothe invention this activity is also ascribed to the molecules namedphosphodiesterase III inhibitors.

Especially in a taste masked form according to the invention,phosphodiesterase III inhibitors, especially pimobendan can be used forhuman and for animal therapy, e.g. by incorporation into a respectivemedical formulation for the treatment of the diseases mentioned above,especially heart diseases, especially of congestive heart failure.

“Cyclooxygenase 2 inhibitors” according to the invention are thosechemical compounds that interact with and inhibit the enzymecyclooxygenase 2 (COX-2), especially those that inhibit COX-2selectively over COX-1. Cyclooxygenase is the enzyme responsible forconverting arachidonic acid into prostaglandin H2, which is the firststep in the synthesis of prostaglandins, which are mediators ofinflammation. Without wishing to be bound by this theory, it is believedthat this specific inhibition leads to an anti-inflammatory effect,accompanied with analgesic and fever reducer effects.

Useful compounds are disclosed by EP 002482 B1. One prominent example ofthese compounds is4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,also known under the INN meloxicam, which is non-steroidal chemicalcompound.

Especially in a taste masked form according to the invention,cyclooxygenase 2 inhibitors, especially meloxicam can be used for humanand for animal therapy, e.g. by incorporation into a respective medicalformulation for the treatment of inflammatory diseases, includinginflammation associated with osteoarthritis, or (other) rheumaticdiseases, as an analgetic and/or as fever reducer.

“Benzodiazepine receptor agonists” according to the invention are thosechemical compounds that interact with and bind to the benzodiazepinereceptor, especially without subtype selectivity. Without wishing to bebound by this theory it is believed, that especially low affinitypartial agonists of the benzodiazepine receptor without subtypeselectivity are effective for the treatment of epilepsy, especially ofidiopathic epilepsy and/or of behavior abnormalities, especiallyanxiety.

Several appropriate compounds are disclosed in WO 97/09314 A1 and WO2005/004867 A2, for example the compound1-(4-chlorophenyl)-4-piperidinoimidazolin-2-one. A preferred compounduseful for this purpose is1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one,disclosed in WO 2004/032938 A1, which has been given the INN imepitoin.

Especially in a taste masked form according to the invention,benzodiazepine receptor agonists, especially imepitoin can be used forhuman and for animal therapy, e.g. by incorporation into a respectivemedical formulation for the treatment of central nervous systemdisorders, esp. epilepsy, idiopathic epilepsy and/or anxiety.

The pharmaceutically active ingredient is regularly incorporated in itschemical form most appropriate for the medical treatment, e.g. assolvate, salt or ester. Especially the salt forms, and among the thesethe forms of the respective hydrochlorides are mostly preferred for theexemplified molecules of1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine,and the monohydrochloride respectively (representative of DPP IVinhibitors) and(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onand/or the respective hydrochloride (representative of i_(f)-channelblockers).

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention described above, further comprisingone or more additional layers between the inert core and/or between oneof the coating layers (b) to (d) and/or on top of coating layer (d).

Such additional layers can be coating layers in the sense of thisapplication, i.e. making up a complete coat or closed film around theparticles underneath, or just a layer of additional material between oron top of the other coating layers.

For example one of the coating layers disclosed herein can be appliedmore than once and thus make up a subject of this aspect of theinvention. Further, e.g. protective layers might be concluded from thestate of the art.

In an alternative, a material is added that does not form a closed filmbut still exerts positive effects. These materials can for example beanti-tacking agents that ameliorate the further processing of therespective particulate material. Such anti-tacking agents are per seknown for the skilled person. They can for example further consist ofpigments, and/or flavors which advantageously be added on top of theouter coating layer (final or taste masking coating). Also suchmaterials are per se known for the skilled person.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the material for the inertcore is cellulose, preferably microcrystalline cellulose.

As explained above, the chemically inert material used for the inertcore can be selected from different materials. A preferred material iscellulose, especially microcrystalline cellulose. Especially thismaterial has turned out to be useful, with respect to the furtherprocessing of the material, but also with respect to the physicalproperties of the finally formulated multi-layered particles. Especiallymicrocrystalline cellulose gives the finally formulated multi-layeredparticles such a degree of flexibility that they can be incorporated ine.g. tablet formulations without destroying them during the compressingstep of the tableting process.

Particles of microcrystalline cellulose can be purchased e.g. under thetrade name Cellets® 100 from the company Syntapharm (Harke Group),Mülheim, Germany.

In another preferred aspect the inert core particles of the arepreferably selected from a pharmaceutically acceptable material whichupon contact with water shows a minimal or negligible swelling.Preferable materials are selected from lactose, carbohydrates, sugaralcohols, such as mannitol, sorbitol, maltitol, glucose,non-pareil-seeds, calcium phosphate, cellulose, preferablymicrocrystalline cellulose (MCC), and starch, and mixtures thereof, morepreferably lactose, most preferably agglomerated α-lactose-monohydrate[Ph.Eur./USP-NF/JP] with a particle size d₅₀ of ca. 180 μm.

Lactose such as agglomerated lactose, with the characteristics describedabove, is also suitable for use in the core because of its particlesize, non-hygroscopicity, and the fact that it at least partly undergoesplastic deformation upon compression so that the core will not breakinto pieces in the tablet press.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the binder for coatinglayer (b) comprising the pharmaceutically active ingredient is selectedfrom HPMC and PVP or a mixture thereof and optionally additionalingredients, preferably the HPMC Hypromellose, USP Substitution Type2910 (apparent viscosity 4.8-7.2 mPas) and/or PVP K30 and optionallyadditional ingredients.

Such materials have already been described above. A preferred materialfor this coating layer (HPMC Hypromellose, USP Substitution Type 2910;apparent viscosity 4.8-7.2 mPas) is commercially available under thetrade name Pharmacoat® 606, sold by Harke Pharma GmbH, Mülheim, Germany.

Alternatively preferred is the material PVP K30 with a molecular weightbetween 44 and 54 kg/mol. Such PVP can be purchased commercially, e.g.by the supplier BASF, Ludwigshafen, Germany, under the trade nameKollidon® 30.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein coating layer (b) comprises80 to 95% (w/w), preferably 82.5 to 90% (w/w), more preferred 84.5 to87.5% (w/w) of the pharmaceutically active ingredient, and 5 to 20%(w/w), preferably 10 to 17.5% (w/w), more preferred 12.5 to 15.5% (w/w)of the binder.

Especially this ratio has turned out to be advantageous for the physicalcharacteristics of the material during its application, on the one hand,and the stability and flexibility of the finally coated particle duringstorage and/or tableting. Variations within these frames are accessiblefor a person skilled in the art.

One other not less preferred mode of the invention is a taste maskedmulti-layered particle according to the invention, wherein coating layer(b) comprises 60 to 70% (w/w) of the pharmaceutically active ingredient,25 to 35% (w/w) of HPMC as binder and 0.5-3% (w/w) magnesium stearate.

Especially in this context magnesium stearate is an advantageouslubricant with a positive influence especially on the coating process.This is documented by the examples. An appropriate magnesium stearate isfor example Parteck® LUB MST, sold by the commercial provider MerckKGaA, Darmstadt, Germany.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the intermediate coatinglayer (seal coating) (c) additionally comprises talc, preferably 10 to30% (w/w) talc, more preferred 15 to 25% (w/w) % talc, most preferred21-23% (w/w) talc.

In another preferred aspect of the invention the said intermediatecoating layer (seal coating) (c) additionally comprises preferably 5 to30% (w/w) talc.

This is applicable to both alternatives of the seal coating that arecomprised by the invention.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the material for theintermediate coating layer (seal coating) (c), (i), HPMC and PEG, isselected from the HPMC Hypromellose, USP Substitution Type 2910(apparent viscosity 2.4-3.6 mPas) and/or PEG 6000.

Especially this material has turned out to be useful for the processitself as well as for the mechanical stability and flexibility of thederived particles. A representative for such a HPMC is commerciallyavailable under the trade name Pharmacoat® 603, sold by Harke PharmaGmbH, Mülheim, Germany. The material PEG has already been explainedabove.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the material for theintermediate coating layer (seal coating) (c), (i) comprises 65 to 75%(w/w) HPMC, 7.5 to 12.5% (w/w) PEG 6000 and 19 to 23% (w/w) talc.

Especially this mixture has proven to be useful as documented by example1.

In another preferred aspect of the invention the said intermediatecoating layer (seal coating) (c) preferably 60 to 90% (w/w) HPMC, 1 to1-15% (w/w) PEG 6000 and 9 to 25% (w/w) talc.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the material for theintermediate coating layer (seal coating) (c), (ii) PVP, is selectedfrom PVP K 30.

Both of these materials have been presented above. Especially thismixture has proven to be useful as documented by example 2.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the material for theintermediate coating layer (seal coating) (c), (ii), comprises 70-80%(w/w) PVP and 20-25% (w/w) talc.

Especially this mixture has proven to be useful as documented by example2.

In another preferred aspect said intermediate coating layer (sealcoating) (c), (ii), comprises 70-95% (w/w) PVP and 5-30% (w/w) talc.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention, wherein the material for the outercoating layer (final or taste masking coating) (d) (i),poly(meth)acrylate, is a basic butylated methacrylate copolymer.

As explained above, several representatives of the polymer class ofpoly(meth)acrylates can be used as integral part of the outer coatinglayer of multi-layered particles according to the invention. However,especially the basic butylated methacrylate copolymer has proven toexert the intended solubility profile, i.e. a high stability around aneutral pH value and the tendency to solve at an acidic pH. This isdocumented by example 1, especially by the measurements that aredocumented by FIGS. 1 to 3, i.e. for the fully formulated multi-layeredparticles as well as for a fully composed tablet comprising suchparticles.

As said above, this polymer can be characterized as a cationic copolymerbased on dimethylaminoethyl methacrylate, butyl methacrylate, and methylmethacrylate with a ratio of 2:1:1, preferably with a molecular weightbetween 40,000 and 50,000, more preferred about 47,000 g/mol. It ispreferably used in its powder form for the suspension to be applied inbuilding up the coating layer.

Such a material is commercially available, e.g. under the trade nameEudragit® E, or Eudragit® E PO in its powder form, from Evonik RöhmGmbH, Business Line Pharma Polymers, Darmstadt, Germany.

In line with the explanations above and as exemplified especially byexample 1 of this specification, the following modes of this aspect ofthe invention are preferred because of the advantageous properties ofthe derived particles with respect to stability, flexibility, usefulnessduring the coating process and last but not least the solubility profilein combination with the effective taste masking: Taste maskedmulti-layered particles according to the invention, wherein the materialfor the outer coating layer (final or taste masking coating) (d) (i)

-   -   comprises 50-80% (w/w) poly(meth)acrylate, 0-8% (w/w) sodium        lauryl sulfate, 0-35% (w/w) stearic acid and/or 0-35% (w/w)        magnesium stearate;    -   comprises poly(meth)acrylate and stearic acid in a weight ratio        of 80:20 to 60:40, more preferred 75:25 to 65:35, most preferred        70:30; and/or    -   makes up a coating level of at least 50% (w/w) (based on the        weight of the particles beneath this coating), preferably 100 to        300% (w/w), more preferred 150 to 250% (w/w), even more        preferred 180 to 220% (w/w), most preferred 190 to 210% (w/w).

Especially the advantageous role of the thickness of this final coatinglayer, based on poly(meth)acrylate, is documented by example 1.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the material for the outercoating layer (final or taste masking coating) (d) (ii), is selectedfrom EC with a viscosity range of 41-49 mPas (measured as 5% solution ina mixture of 80% toluene and 20% ethanol and an ethoxyl content of48.0-49.5%) and/or HPMC with a methoxyl content of 28-30%, ahydroxypropyl content of 7-12% and a viscosity range of 4-6 mPas(measured as 2% solution in water).

The usefulness of this alternative taste masking coating with theseselected materials has been proven by example 2 of this specification.

An appropriate EC (ethylcellulose) for is for example the productEthocel® 45 cps STD Premium, sold by the commercial provider DowChemicals, Schwalbach, Germany. An appropriate magnesium stearate forthis taste masking coating is for example Parteck® LUB MST, sold by thecommercial provider Merck KGaA, Darmstadt, Germany.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the material for the outercoating layer (final or taste masking coating) (d) (ii), comprises50-75% (w/w) EC, 15-40% (w/w) HPMC and 0-25% (w/w) magnesium stearate,preferably 50-60% (w/w) EC, 20-25% (w/w) HPMC and 17.5-22.5% (w/w)magnesium stearate.

Examples for such coatings are given in following table 1, along withpreferred suspensions for the application of such material, i.e. byspraying onto the respective not covered particles (so called “SCpellets” according to Example 1) employing a fluid bed based process.Alternative experimental settings are equally preferred. Each compoundis further explained to exert special physicochemical functions; theseare assumptions up to the best knowledge at the time being but notintended to limit the scope of the protection.

TABLE 1 Composition of EC/HPMC/magnesium stearate film coat (aqueous andorganic solvent process), as alternative taste and/or odor maskingcoating Amount of respective Function of respective component Solventprocess Component component [% (w/w)] 1 aqueous EC functional coatingca. 52.2 (EC/HPMC HPMC pore former ca. 34.8 60:40) Magnesiumanti-tacking agent, ca. 13 stearate reduction of electrostatic charging2 aqueous EC functional coating ca. 69.6 (EC/HPMC HPMC pore former ca.17.4 80:20) Magnesium anti-tacking agent, ca. 13 stearate reduction ofelectrostatic charging 3 organic EC functional coating ca. 52.2 (EC/HPMCHPMC pore former ca. 34.8 60:40) Magnesium anti-tacking agent, ca. 13stearate reduction of electrostatic charging 4 organic EC functionalcoating ca. 69.6 (EC/HPMC HPMC pore former ca. 17.4 80:20) Magnesiumanti-tacking agent, ca. 13 stearate reduction of electrostatic charging

A preferred mode of this aspect of the invention is made up by tastemasked multi-layered particles according to this aspect, wherein thematerial for the outer coating layer (final or taste masking coating)(d) (ii) makes up a coating level of at least 25% (w/w) (based on theweight of the particles beneath this coating), preferably 25 to 100%(w/w), more preferred 50 to 90% (w/w), even more preferred 70 to 80%(w/w), most preferred 72.5 to 77.5% (w/w).

Representatives with these values are described in example 2.

One preferred mode of this aspect of the invention is a taste maskedmulti-layered particle according to the invention, wherein the outercoating layer (final or taste masking coating) (d) of the particle ischaracterized in mode (i) (poly(meth)acrylate) by a thickness of 50 to150 μm, preferably 60 to 140 μm, more preferred 70 to 130 μm, even morepreferred 75 to 125 μm, most preferred 77 to 119 μm, or in mode (ii)(mixture comprising EC and HPMC) by a thickness of 10 to 150 μm,preferably 12 to 120 μm, more preferred 15 to 100 μm, most preferred 20to 50 μm. All of these values are to be understood with a variance of±10 μm.

As described in example 1 for outer coatings of mode (i)(poly(meth)acrylate) such an outer coating is obtainable by a finalcoating step using an aqueous coating solution and a coating level of200% with a variance of ±10 μm. Such particles show an advantageoustaste-masking effect accompanied with an advantageous dissolutionprofile and are therefore preferred embodiments. Variations of theprocess, esp. the use of an organic solvent and/or different coatinglevels can be applied by a person skilled in the art in order to reachthe other named values of thickness of the respective outer coatinglayers (final or taste masking coating) (d) (i) and (ii), respectively.Such particles are equally preferred.

As said above, multi-layered particles according to the invention cancomprise additional layers that can be coating layers in the sense ofthis application, i.e. making up a complete coat or closed film aroundthe particles underneath, or just a complete or incomplete layer ofadditional material between or on top of the other coating layers.

One preferred mode of this aspect of the invention pertains to tastemasked multi-layered particles according to the invention, wherein theone or more additional layers between the inert core and/or between oneof the coating layers (b) to (d) and/or on top of coating layer (d)comprise(s) colloidal siliciumdioxide (silica), preferably 0.1-5% (w/w)(based on the weight of the final particles), more preferred 0.2-2.5%(w/w), most preferred 0.2-1% (w/w).

As exemplified by example 2, it has been found advantageous to add suchmaterial on top of the particles during the production process afterdrying of one coat and before the addition of the next coat, especiallyas anti-tacking agent.

One preferred mode of this aspect of the invention pertains to tastemasked multi-layered particles according to the invention, wherein anadditional coating layer(s) is a final outer-coating on top of coatinglayer (final or taste masking coating) (d) and the material for thisadditional coating layer(s) is selected from HPMC with a methoxylcontent of 28-30%, a hydroxypropylcontent of 7-12% and a viscosity rangeof 4-6 mPas (measured as 2% solution in water).

This has been found very advantageous for multi-layered particles thatare intended for the incorporation into overall liquid formulations,esp. oily liquid pharmaceutical compositions. The additional layerserves two purposes: (i) a mechanical protection against the otherparticles in the suspension and (ii) an additional protection againstwater that might tend to diffuse through the oily suspension into theparticles.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein one or more of the layermaterial(s) comprise(s) additional substances, preferably fillersubstances, binders, wetting agents, glidants, lubricants, dispersingagents, coloring agents and/or anti-tacking agents, selected from one ormore of: mannitol, starch, talc, titaniumdioxide, sodium lauryl sulfate,sodium dodecylsulfate, stearic acid, magnesium stearate, silica andmedium chain triglycerides.

In addition, preferred taste masked multi-layered particles according tothe invention are those, wherein one or more of the layer material(s),preferably for one of the seal coating and/or final coating comprise(s)additional substances selected from flavoring agents, pigments andsubstances for the reduction of electrostatic charging, more preferredmeat flavor, pigments and/or siliciumdioxide.

For example, it has been found advantageous to choose an anti-tackingagent, preferably magnesium stearate, e.g. magnesium stearate ParTeck®LUB MST, commercially available, e.g. by the supplier Merck KGaA,Darmstadt, Germany, as an additional ingredient for coating layer (b).The optionally incorporated anti-tacking material can advantageously beadded in the form of a suspension in a solvent, e.g. suspended in thesolution/suspension used for the adding of the respective coating layerduring the respective coating step. Alternatively it can be added in theform of a powder onto the dried particles after the respective layer isbuilt up and dried.

In another/additional preferred mode of the invention the material forthe intermediate coating layer (seal coating) (c) additionally comprisestalc and/or magnesium stearate.

For the outer coating layer it has been found advantageous when theapplied poly(meth)acrylate component is blended with magnesium stearateas anti-tacking agent, which combination is especially useful when anorganic solvent process is used for the application of this coating ontothe respective particles. Talc and/or colloidal silica (siliciumdioxide)can optionally be added to counteract electrostatic charging.

In the alternative approach when the poly(meth)acrylate coating isapplied by an aqueous process, it is preferred to form a total mixturecomprising sodium lauryl sulfate (as wetting and dispersing agent),stearic acid (as salt former and further for forming a colloidalsolution with poly(meth)acrylate) and/or magnesium stearate (asanti-tacking agent). Alternative anti-tacking agents are for exampletalc and/or silica. Talc and/or colloidal silica can optionally furtherbe added to counteract electrostatic charging.

Coloring agents may include but are not limited to titanium dioxide, anddyes suitable for food and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, etc. The amount of coloring agent used may range from about0.05 to about 3.5%(w/w) of the total dosage form.

However, as discussed above, the feature “free from a low molecularweight water-soluble ionic compound” is limiting. The selection of suchcompounds is limited by their ability to dissolve in water, as explainedabove.

Further, not less preferred embodiments of the invention pertain totaste masked multi-layered particles according to the invention,wherein:

-   -   the inert core is characterized by a diameter of 50 to 300 μm,        preferably 75 to 250 μm, more preferred 100 to 200 μm;    -   wherein the final coated particle is characterized by an overall        diameter of 80 to 800 μm, preferably 90 to 600 μm, more        preferred 100 to 400 μm; and/or    -   wherein the pharmaceutically active ingredient in its        incorporated chemical form makes up 1 to 50% (w/w) of the final        multi-layered particle, preferably 2 to 25% (w/w), more        preferred 3 to 22.5% (w/w) and most preferred 5 to 20% (w/w).

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the pharmaceutically activeingredient (a) (a DPP IV inhibitor) is selected from1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthineor any appropriate form and/or salt thereof, preferably1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride.

This compound has been found to be an appropriate compound for thetreatment of metabolic diseases via the addressed target DPP IV. On theother hand it is water-soluble, especially in its salt form, and ischaracterized by a bitter taste that tends to be rejected especially byanimal patients. Accordingly, there was a need to taste mask thiscompound. As documented by example 1, the invention disclosed hereallows an effective taste masking of this compound so that it can beapplied for a wide range of patients now.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride as pharmaceutically active ingredient, comprising:

-   a) an inert core comprising microcrystalline cellulose,-   b) two coating layer(s) each of them comprising 60 to 90% (w/w) of    the pharmaceutically active ingredient and 10 to 40% (w/w) of HPMC    as binder,-   c) an intermediate coating layer (seal coating) comprising 65 to 75%    (w/w) HPMC, 7.5 to 12.5% (w/w) PEG 6000 and 19 to 23% (w/w) talc and-   d) an outer coating layer (final or taste masking coating)    comprising 50-80% (w/w) basic butylated methacrylate copolymer, 5-8%    (w/w) sodium lauryl sulfate, 8-35% (w/w) stearic acid and 18-26%    (w/w) magnesium stearate,    wherein the material for the outer coating layer (d) (final or taste    masking coating) makes up a coating level of 190 to 210% (w/w).

Such a multi-layered particle as well as a method for its production aredemonstrated by example 1. The process described there is summarized inthe flow chart of table 2.

As can be seen in table 2, the layering of the pharmaceutically activeingredient can be divided into two steps. Regardless of the identity ofthe compound, this is generally preferred when a high drug load has tobe achieved. This might especially be due to technical reasons, i.e. totechnical parameters of the fluid bed apparatus, as each employed fluidbed process equipment has a certain minimum/maximum loading capacity.Each process therefore can only be operated until a certain point beforethe maximum loading capacity is reached. For example in case of1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride the maximum loading capacity is reached when the massof the material has increased to approx. 300% based on the amount thatwas originally employed, i.e. has reached 3 times the weight of thestarting material.

It might also be possible and with no significant effect for the productquality to split each processed material into two or more sub-batchesthat are further processed separately. For example the pellets producedin the first coating step (so called IR1 pellets, according toexample 1) can be split into sub-batches which are again layered withdrug until a several-fold (in this case three-fold) mass increase isreached. The two or more sub-batches are then mixed and furtherprocessed together, or again split into sub-batches, depending on thescale of equipment that is selected for the next coating steps.

As further demonstrated by example 1, it is possible to apply the sealcoating byway of an aqueous process. Despite the risk that the drugmigrates into the outer layers of the seal coating during the process,the finally resulting multi-layered particles turned out to be usefulfor the treatment of cats which did not refrain from ingesting thederived pharmaceutical form.

Example 1 discloses a multi-layered particle comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydro chloride with a taste masking coating based on basic butylatedmethacrylate copolymer, comprising 62.5% (w/w) basic butylatedmethacrylate copolymer (Eudragit® E PO), 6.2% (w/w) sodium laurylsulfate, 9.3% (w/w) stearic acid and 21.9% (w/w) magnesium stearate,added in aqueous solution, to a total amount of around 200% soliddeposit (percentage based on the amount of “SC pellets” startingmaterial).

It was surprising to find that even with this highly water solubleactive substance, all drug layering and polymer coating steps could beperformed using aqueous as well as organic solvent coating processeswithout the bitter active ingredient migrating up to a critical extentinto the outer polymer layers. This was proven by SEM coupled withx-ray/EDS (Energy Dispersive X-ray analysis).

The total composition of final taste masked multi-layered particlesaccording to the invention comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride as active ingredient, produced by the outlined steps 1to 4 of example 1, is given in table 5. It represents a preferred aspectof the invention. Certain functions that can most probably be ascribedto the respective components have also been listed there; however, thisdoes in no way limit the scope of the invention.

The data of example 1 reveal that multi-layered particles coated withbasic butylated methacrylate copolymer exhibit an increasingly delayedrelease at pH 6.8, depending on the coating thickness, and an immediaterelease at pH 1. Accordingly, they are able to mask effectively thetaste of a pharmaceutically active ingredient in the oral cavity (pH6.8) while facilitating immediate drug release in the stomach (pH 1).

Especially particles coated with basic butylated methacrylate copolymerat a coating level of about 200% and/or a thickness of 77 to 119 μm ofthe outer coating layer (d) show the desired drug release profile,irrespective of the solvent used in the coating process.

A preferred mode of this aspect is a taste masked multi-layered particleas described before, wherein the pharmaceutically active ingredient inits incorporated chemical form makes up 5 to 25% (w/w) of the finalmulti-layered particle (calculated as free base), preferably 10 to 23%(w/w), more preferred 18 to 22% (w/w), most preferred 20 to 21% (w/w).

Such values have turned out to be useful with respect to the potency ofthe compound, on the one hand, and the need to design pharmaceuticalcompositions with favorable concentrations of the active ingredient.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the pharmaceutically activeingredient ((3) (an i_(f)-channel blocker) is selected from zatebradine(1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane),3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on,its enantiomer cilobradine((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on)or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), mostlypreferred cilobradine hydrochloride((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onhydrochloride).

These compounds, especially cilobradine and cilobradine hydrochloride,have been found to be appropriate compounds for the treatment of heartdiseases, especially for the treatment of heart failure, via theaddressed target, the i_(f)-channel. On the other hand it iswater-soluble, especially in its salt form, and has got a bitter tastethat tends to be rejected especially by animal patients. Accordingly,there was a need to taste mask this compound. As documented by example2, the invention disclosed here allows an effective taste masking ofthis compound, accompanied by a useful dissolution profile in thepatient's mouth or intestine, so that it can be applied for a wide rangeof patients now.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention comprising cilobradine hydrochlorideas pharmaceutically active ingredient comprising:

-   a) an inert core comprising microcrystalline cellulose,-   b) one coating layer comprising 60 to 70% (w/w) of the    pharmaceutically active ingredient, 25 to 35% (w/w) of HPMC as    binder and 0.5-3% (w/w) magnesium stearate,-   c) an intermediate coating layer (seal coating) comprising 70-80%    (w/w) PVP K 30, 20-25% (w/w) talc and 0.5-5% (w/w) siliciumdioxide    and-   d) an outer coating layer (final or taste masking coating)    comprising a mixture comprising 50-60% (w/w) EC, 20-25% (w/w) HPMC,    17.5-22.5% (w/w) magnesium stearate and 0.5-3% (w/w)    siliciumdioxide,    wherein the material for the outer coating layer (d) (final or taste    masking coating) makes up a coating level of 72.5 to 77.5% (w/w).

Such a multi-layered particle as well as a method for its production aredemonstrated by example 2. The process described there is summarized inthe flow chart of table 10.

Like described before, the coating may generally be applied by anaqueous or an organic solvent spraying process, which can be optimizedexperimentally. In the case of this compound it was found to bepreferable to add the coating layer comprising the pharmaceuticallyactive ingredient by ways of an aqueous solution and the next two layersby ways of an organic solution, the solvent for the intermediate coatingstep being a mixture of 94.4% (v/v) acetone and 5.6% (v/v) ethanol, thesolvent for the final coating step composed of a 1:1 mixture (v/v) ofmethanol and dichloromethane, due to the high solubility of the drug inwater.

The thickness of the outer coating layer (final or taste maskingcoating) may be varied between e.g. 50-300% solid deposit (percentagebased on the initial amount of the respective SC pellets as defined inthe cited example), in order to achieve the desired dissolutionbehaviour. In this example, it was found to be sufficient to apply thefinal coating to a thickness of about 75% based on the initial amount ofSC pellets (result of step 2) employed in the process.

According to the dissolution data collected in example 2, thedissolution from EC/HPMC coated pellets is delayed, therefore providingefficient taste and/or odor masking of the bitter active ingredientcilobradine hydrochloride. This could be verified by acceptance testswith laboratory cats.

Usually, EC/HPMC films show a sustained release behavior more or lessindependent of pH. In this case, however, the product surprisinglyshowed a slower release at pH 6.8 which is favorable with regards to theinvention, i.e. providing efficient taste masking in the oral cavity anda faster release in the acidic stomach. Without wishing to be bound bythis theory, this may be explained by the lipophilicity profile of thespecific pharmaceutically active ingredient, which is slightly morelipophilic at neutral pH values than at acidic pH values. This, togetherwith the coating applied, is expected to result in a slower release atneutral pH values, sufficient to use the respective multi-layeredparticles for the application of this drug for the treatment ofpatients, esp. of animals like cats.

A preferred mode of this aspect is a taste masked multi-layered particleas described before, wherein the pharmaceutically active ingredient inits incorporated chemical form makes up 2 to 10% (w/w) of the finalmulti-layered particle (calculated as hydrochloride), preferably, 3 to7.5% (w/w), more preferred 4 to 6% (w/w), most preferred 5.25 to 5.75%(w/w).

Such values have turned out to be useful with respect to the potency ofthe pharmaceutically active ingredient, on the one hand, and the need todesign pharmaceutical compositions with favorable concentrations of theactive ingredient.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the pharmaceutically activeingredient (γ) (a phosphodiesterase III inhibitor) is pimobendan((RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one).

In line with the explanations above, this compound is useful for thetreatment of heart diseases via the addressed target phosphodiesteraseIII. On the other hand it was desired to be taste masked. According tothe underlying invention it is now possible to use this compoundespecially for oral medications, especially of taste sensitive animalslike cats or dogs.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the pharmaceutically activeingredient (δ) (a cyclooxygenase 2 inhibitor) is meloxicam(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide).

In line with the explanations above, this compound is especially usefulfor the treatment of inflammatory diseases via the addressed targetcyclooxygenase 2. On the other hand it was desired to be taste masked.According to the underlying invention it is now possible to use thiscompound especially for oral medications, especially of taste sensitiveanimals like cats or dogs.

One preferred mode of the invention is a taste masked multi-layeredparticle according to the invention wherein the pharmaceutically activeingredient (ε) (a benzodiazepine receptor agonist) is selected from1-(4-chlorophenyl)-4-piperidinoimidazolin-2-one and imepitoin(1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one),preferably imepitoin.

In line with the explanations above, compounds of this group are usefulfor the treatment of central nervous system disorders, like epilepsy,especially idiopathic epilepsy, and behavioural abnormalities, esp.anxiety, of human and of animal patients via the addressedbenzodiazepine receptor. On the other hand it was desired to be tastemasked. According to the underlying invention it is now possible to usethis compound especially for oral medications, especially of tastesensitive animals like dogs.

One aspect of the present invention resides in methods for theproduction of multi-layered particles according to the invention, inwhich the coating layers are assembled stepwise, starting from thematerial for the inert core, the single coating steps separated bydrying steps.

As explained above, methods for the granulation process, i.e. for thesubsequent addition of layers onto a smaller particle are per se knownto the person skilled in the art. The claimed process starts with thecore material, and the respective layer materials are added subsequentlybeginning with the innermost layer material. Each coating material ispreferably added in liquid form, i.e. as a solution or suspension in afluid carrier like water or other suitable solvents like ethanol oracetone or mixtures thereof, which liquid is allowed to dry subsequentto its application and before the next layer is added. The addition inpowder form is also possible and especially appropriate for the finaloutermost layer or for additional intermediate layers.

With respect to the application of the intermediate coating layer (sealcoating) (c) and of the outer coating layer (final or taste maskingcoating) (d), especially of the outer coating layer, it has been foundthat the intended coating materials are preferably applied to therespective particles in the form of a liquid solution or suspension inan appropriate solvent. This solvent can be selected from (purified)water or organic solvents like acetone, methanol, ethanol ordichloromethane or mixtures thereof. While the use of water iscost-efficient, the use of organic solvents may have the advantage of afaster drying step, thus shortening the time for the active ingredientto diffuse into the respective layer. Further, the choice of an organicsolvent is especially preferred for pharmaceutically active ingredientswith a high dissolution rate in water. The organic solvent then furtherhinders the diffusion of the active substance into outer layers duringthe layering step. Thus, by using organic solvents, it is possible tominimize migration of the active substance and thereby to ensure a veryeffective taste and/or odor masking. In addition, the layers that areproduced with an organic solvent may be more tight than those producedwith water and have an overall more even appearance. These howeversubtle differences may be exploited if the particles need to beoptimized with respect to their dissolution behaviour vs. barrierfunction.

This effect is exemplified by the two examples of this application: thechoice of both, water and organic liquids as a solvent, for theoutermost layer of multi-layered particles comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride as active ingredient are possible, with respect to theeffect that an animal will not taste the respective active ingredient.

For the preparation of multi-layered particles comprising the drugcilobradine hydrochloride is has been found to be the best solution toapply the two outermost layers (i.e. the seal coating and the finalcoating) by use of organic solvents.

A person skilled in the art is able to analyze this effect and to modifythe solvent, which might include the choice of an appropriate solventmixture. For example the technique of Energy Dispersive X-ray analysis(EDS) can be used for analyzing to which extent the pharmaceuticallyactive ingredient might still be present in the respective outer coatinglayer. This can be applied to the finally composed particles as well asfor monitoring the production process by analyzing samples taken duringthe process.

A preferred method takes place in a fluid bed, preferably a Wursterfluid bed coating process (Wurster process).

Such a fluid bed is formed usually in a holding vessel when the solidparticulate material is placed under appropriate conditions to cause themixture to behave as a fluid. This is usually achieved by theintroduction of pressurized fluid or gas like air through theparticulate medium. This results in the medium then having manyproperties and characteristics of normal fluids, such as the ability tofree-flow under gravity, or to be pumped using fluid type technologies.According to the invention the fluid bed can be used to spray thecoating suspensions into the particulate material in order to achieve anoverall tight coating layer around each particle.

Such a process is per se known to a person skilled in the art and can beapplied with the aims and limitations given herein.

One preferred mode of the invention is such a method according to theinvention, wherein the material for the outer coating layer (d) (i)(final or taste masking coating) is added to an amount of at least 50%(w/w) (based on the weight of the particles to be coated in this step),preferably 100 to 300% (w/w), more preferred 150 to 250% (w/w), evenmore preferred 180 to 220% (w/w), most preferred 190 to 210% (w/w).

As documented by example 1, this mode is especially advantageous for theaddition of an coating layer (d) (i) (final or taste masking coating)that comprises poly(meth)acrylate or a comparable material, preferablybasic butylated methacrylate copolymer, as explained above. It allows agood stability of the produced multi-layered particles, combined with agood dissolution profile.

One preferred mode of the invention is such a method according to theinvention, wherein the material for the outer coating layer (d) (ii)(final or taste masking coating) is added to an amount of at least 25%(w/w) (based on the weight of the particles beneath this coating),preferably 25 to 100% (w/w), more preferred 50 to 90% (w/w), even morepreferred 70 to 80% (w/w), most preferred 72.5 to 77.5% (w/w).

As documented by example 2, this mode is especially advantageous for theaddition of an coating layer (d) (i) (final or taste masking coating)that comprises a mixture comprising 60-90% (w/w) ethylcellulose (EC) and10-40% (w/w) HPMC, and respectively preferred embodiments thereof, asexplained above.

As can be seen from the examples and the description above, it is onemajor achievement of the invention to provide coating materials that canbe used for specific coating layers of particles comprising specificpharmaceutically active ingredients in order to exert an effective tastemasking, accompanied with advantageous dissolution profiles andmechanical characteristics. Such advantageous coating materials and/orspecific mixtures thereof have been developed for intermediate coatinglayers (seal coating) of such multi-layered particles as well as forouter coating layers (final or taste masking coating) of suchmulti-layered particles.

Accordingly, one aspect of the invention pertains to the use of

-   -   (i) a mixture comprising hydroxypropyl methylcellulose (HPMC)        and polyethylene glycol (PEG) or    -   (ii) poly(1-vinylpyrrolidin-2-one) (PVP),        for the assembly of an intermediate coating layer (seal        coating) (c) free from a low molecular weight water-soluble        ionic compound of a multi-layered particle according to the        invention.

Multi-layered particles comprising such materials for intermediatecoating layers (seal coating) are exemplified by the examples and proveto be taste-masked, especially in combination with outer coating layers(final or taste masking coating) according to the invention.

One preferred use according to this aspect is a use wherein the materialfor the intermediate coating layer (seal coating) (c) (i) comprises 65to 75% (w/w) HPMC, 7.5 to 12.5% (w/w) PEG 6000 and 19 to 23% (w/w) talc.

An alternative, not less preferred use according to this aspect is a usewherein the material for the intermediate coating layer (seal coating)(ii) comprises 70-80% (w/w) PVP and 20-25% (w/w) talc.

The advantages of such uses are presented in the examples and can beunderstood in the light of the description above. These are especiallypersistent in combination with the uses of further appropriate materialfor the outer coating layer according to the invention.

One equally preferred aspect of the invention pertains to the use of

-   -   (i) poly(meth)acrylate or    -   (ii) a mixture comprising 60-90% (w/w) EC and 10-40% (w/w)        hydroxypropyl methylcellulose (HPMC),        for the assembly of an outer coating layer (final or taste        masking coating) (d) free from a low molecular weight        water-soluble ionic compound of a multi-layered particle        according to the invention.

Multi-layered particles comprising such materials for outer coatinglayers (final or taste masking coating) are exemplified by the examplesand prove to be taste-masked, especially in combination withintermediate coating layers (seal coating) according to the invention.

One preferred use according to this aspect is a use wherein the materialfor the outer coating layer (final or taste masking coating) comprisesadditional substances selected from flavoring agents, pigments andsubstances for the reduction of electrostatic charging.

For these allow the production of multi-layered particles according tothe invention with the respective advantages of these materials thathave already been explained above.

One preferred use according to this aspect is a use wherein the materialfor the outer coating layer (d) (i) (final or taste masking coating withpoly(meth)acrylate) is added to an amount of at least 50% (w/w) (basedon the weight of the particles to be coated in this step), preferably100 to 300% (w/w), more preferred 150 to 250% (w/w), even more preferred180 to 220% (w/w), most preferred 190 to 210% (w/w).

As explained above and documented by example 1, this mode allows a goodstability of the produced multi-layered particles, combined with a gooddissolution profile.

One not less preferred use according to this aspect is a use wherein thematerial for the outer coating layer (d) (ii) (final or taste maskingcoating with a mixture comprising 60-90% (w/w) EC and 10-40% (w/w) HPMC)is added to an amount of at least 25% (w/w) (based on the weight of theparticles beneath this coating), preferably 25 to 100% (w/w), morepreferred 50 to 90% (w/w), even more preferred 70 to 80% (w/w), mostpreferred 72.5 to 77.5% (w/w).

As explained above and documented by example 2, this mode allows a goodstability of the produced multi-layered particles, combined with a gooddissolution profile.

One aspect of the present invention provides the use of multi-layeredparticles according to the invention, for the treatment of

-   α) a metabolic disease, via DPP IV as target,-   β) a heart disease, via the i_(f)-channel as target,-   γ) a heart disease, via phosphodiesterase III as target,-   δ) an inflammatory disease via cyclooxygenase 2 as target and/or    ε) a disease of the central nervous system via the benzodiazepine    receptor as target.

Particles including respective pharmaceutically active ingredientscomprised by them, are disclosed above. According to this aspect of theinvention they can be used per se via oral application, i.e. withoutfurther excipients for the treatment of patients. For example they canbe added to the food. Such a use has been made accessible by theinvention of the multi-layered particles according to the inventionbecause they are physically very stable, generally so stable that theystay intact even if the patient bites on it, e.g. during the ingestionof the food stuff

A preferred use according to this aspect of the invention is such a usefor the treatment of an animal.

For this purpose an appropriate amount of the respective material can beadded to the animal's food stuff, e.g. by the persons taking care forthe animals. This is very advantageous if the pharmaceutically activeingredient is intended to be used at a low dosage for prophylaxisagainst the respective diseases.

It is preferred that the particles used in this way comprise appropriateflavors in the outer coating. For example it has turned out to be usefulto apply meat flavors in order to make the particles attractive forcarnivorous animals.

One aspect of the present invention provides compositions comprising amulti-layered particle according to the invention.

In one aspect the present invention provides pharmaceutical compositionscomprising a multi-layered particle according to the invention for theuse in a method for the treatment of

-   α) a metabolic disease, via DPP IV as target,-   β) a heart disease, via the i_(f)-channel as target,-   γ) a heart disease, via phosphodiesterase III as target,-   δ) an inflammatory disease via cyclooxygenase 2 as target and/or-   ε) a disease of the central nervous system via the benzodiazepine    receptor as target.

In general, the multi-layered particles according to the invention canbe incorporated in all forms of pharmaceutical compositions appropriatefor the treatment of the respective diseases, preferably for oraladministration. They can especially be incorporated into solid dosageforms like tablets as well as into predominantly liquid (e.g. oilysuspensions) or pasteous dosage forms. Liquid or pasteous dosage formsin general offer the option of very flexible dosing by adjusting theadministered volume. Tablets comprising multi-layered particlesaccording to the invention can be divided without damaging theprotective layer, hence also providing a possibility for dose adaption,e.g. by forming score lines.

It has been shown in acceptance tests that both, oily suspensions aswell as tablets (both flavored) containing multi-layered particleaccording to the invention, lead to the desired result: they are verywell accepted by the patients (exemplified by cats) and are in themajority of cases ingested voluntarily.

With respect to this aspect of the invention, the multi-layeredparticles are preferably sized in a way to generate an acceptable mouthfeel for the patient (e.g. the cat), meaning: they are not be too big asthat would lead to a gritty sensation which would lower the acceptanceby the patient. Especially for the use in tablet mixtures, particlesaccording to the invention are preferred that possess sufficientmechanical stability to resist compression as well as breaking orchewing of the resulting tablets. The film coating has preferablysufficient flexibility to allow deformation during a standardcompression process.

Basically all sorts of additive materials that are suitable for suchpharmaceutical dosage forms can be mixed with the multi-layeredparticles according to the invention in order to prepare a finallycomposed pharmaceutical, with respect to the envisaged application routeand dosage regime of the respective patient group.

One preferred mode of the invention is a pharmaceutical compositionaccording to the invention in solid form, preferably a capsule or tabletwith a mass of 20 to 4000 mg per unit, more preferred 20 to 500 mg perunit, even more preferred 30 to 400 mg per unit, most preferred 40 to300 mg per unit.

Solid dosage forms preferably comprise excipients that support theintended medical effect. Such other excipients are in general known to aperson skilled in the art. Useful excipients are for exampleantiadherents (used to reduce the adhesion between the powder (granules)and the punch faces and thus prevent sticking to tablet punches),binders (solution binders or dry binders that hold the ingredientstogether), coatings (to protect further tablet ingredients fromdeterioration by moisture in the air and make large orunpleasant-tasting tablets easier to swallow), disintegrants (to allowthe tablet to break upon dilution), fillers, diluents, flavours,colours, glidants (to promote powder flow by reducing interparticlefriction and cohesion), lubricants (to prevent ingredients from clumpingtogether and from sticking to the tablet punches or capsule fillingmachine), preservatives, sorbents, sweeteners etc.

Preferred carriers and/or disintegrants are selected from the group ofsugars and sugar alcohols, e.g. mannitol, lactose, starch, cellulose,microcrystalline cellulose and cellulose derivatives, e. g.methylcellulose, and the like.

Preferred binders are selected from the group consisting of polyvidone(used synonymously for povidone), methylcellulose,hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, starch,gelatine, and the like.

Preferred ingredients are one or several flow regulators, e.g. selectedfrom the group consisting of silica, preferably colloidal anhydroussilica, calcium silicate, magnesium silicate, talc, and the like.

Preferred disintegrants are selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, pregelatinised starch,cross-linked polyvinylpyrrolidone and the like.

Preferred lubricants selected from the group consisting of magnesiumstearate, calcium stearate, glyceryl behenate, polyethylene glycol,stearic acid, talc and the like.

Preferred carriers are mannitol, starch and/or lactose. The carriermaterial can consist of coarse particles greater than 200 μm in size,equal or smaller than 200 μm in size, or spray-dried material.

Preferred starches are selected from the group consisting of corn(maize) starch, native starch, gelatinized starch, partly gelatinizedstarch, starch powder, starch granules, chemically modified starch andswellable physically modified starch.

As explained above, especially for the use in tablet mixtures, particlesaccording to the invention have turned out to possess regularlysufficient mechanical stability to resist compression as well asbreaking or chewing of the resulting tablets.

In order to secure these characteristics, it is preferred to incorporatemulti-layered particles according to the invention with the followingfeatures:

-   -   a size of the finally coated multi-layered particle between        0.08-0.8 mm, preferably 0.1-0.4 mm;    -   applying a coating with sufficient flexibility, which can be        based on the physical parameters of the polymer or by using        appropriate plasticizers in appropriate amounts; and/or    -   the use of microcrystalline cellulose pellets as core material,        as these will undergo plastic deformation upon compression.

Further it is preferred to use an appropriate composition of thetableting mix—i.e. preferably using tableting excipients that undergoplastic deformation and ensuring that the mass ratio of coated pelletsin the tableting mix does not exceed 50%, as demonstrated in theexamples of this specification.

Such variations lie well within the ambit of the skilled person.

It is preferred to achieve a high load of the active ingredient (drugload) on the particles, because this influences the final size of thetablet. On the other hand a too high amount of multi-layered particlesin the tableting mix could lead to an insufficient compressibility ofthe mix, resulting in mechanical instability of the tablets and anincreased risk of disruption of the film due to excessive deformation ofthe pellets. Moreover, tablet disintegration and drug dissolution may bechanged in an undesired way, e.g. too slow disintegration due to“sticking” of the pellets and/or too fast drug release than intendedbecause of damages to the film.

The production of a pharmaceutical composition comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride as pharmaceutically active ingredient is demonstratedby example 1, which in detail discloses the production of multi-layeredparticles containing the pharmaceutically active ingredient whichparticles were incorporated into a tablet formulation ready for thetreatment of a patient.

An example of a completely composed tablet matrix and thus a preferredmode of carrying out the invention is disclosed in example 1. Inaddition to the drug containing multi-layered particles, the shownpharmaceutical composition contains other materials that are per seknown from the state of the art and that can be adapted with respect tospecific requirements, with respect to their nature as well as withrespect to their concentration. This preferred collection of substancesis intended to serve as filler and/or binder, disintegrant, flavoringagent, pigment, glidant and lubricant, respectively, as outlined intable 8. These functions correspond to the best knowledge at the timebeing but are in no way limiting the scope of the invention.

This composition contains especially a flavoring agent to render thetablets attractive to carnivorous animals. Especially this ingredientmight be adapted with respect to the need of the pharmacists. Forexample, dogs and/or cats might prefer the meat flavor; other notpredominantly carnivorous animals or humans might prefer another one.

As demonstrated by this example, multi-layered particles as well aspharmaceutical compositions, especially compressed tables comprising themulti-layered particles according to the invention fulfill allrequirements regarding drug load and dissolution behavior. Especiallythe aqueous coating process for the final coating as described inexample 1 worked surprisingly well with the water soluble drug substance1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride.

One preferred mode of the invention is a solid pharmaceuticalcomposition according to the invention, comprising the pharmaceuticallyactive ingredient in a final concentration of 0.1 to 1000 mg per unit,preferred 2 to 50 mg per unit, even more preferred 3 to 40 mg per unit,most preferred 4 to 30 mg per unit.

This has turned out to be useful for the intended therapy, e.g. the onesthat are accessible by the preparations of the examples. The appropriateconcentration can be adapted by a person skilled in the art with respectto the intended treatment and the patient group to be treated.

One preferred mode of the invention is a solid pharmaceuticalcomposition according to the invention, in the form of a tablet,preferably a tablet with one or more score lines to be split intopieces.

The advantages of the tablet form have been explained above. Thepresence of one or more score lines on/in these tablets allows that thetablets be split into pieces in order to adapt the applied amount of thepharmaceutically active ingredient. This is especially worthy when adiverse patient population is envisaged, like companion animals that arecharacterized by a great number of races varying drastically withrespect to the individual size, like dogs.

Another preferred mode of the invention is a pharmaceutical compositionaccording to the invention in overall liquid form.

In some cases it is advantageous to prepare a pharmaceutical compositionin a liquid formulation because this dosage form ensures a very precisedosing of the respective drug. Multi-layered particles according to theinvention can be used for this application form.

The composition of an appropriate liquid formulation is per se known toa person skilled in the art. As exemplified by example 2, it isadvantageous and accordingly preferred to use a mixture of triglyceridesas basis and to add hydrophilic and/or hydrophobic colloidal silica inorder to optimize the physicochemical properties of the composition.

Especially preferred is a mixture of hydrophilic and hydrophobiccolloidal silica which ensures an appropriate viscosity behaviour of thesuspension that remains more or less unchanged over the storage period.Commercially available siliciumdioxides (silica) are for exampleAerosil® 200 (hydrophilic) and Aerosil® R972 (hydrophobic), both soldunder these respective trade names by Evonik Röhm, Darmstadt, Germany.

During storage, such a suspension preferably exhibits a high viscosity,preventing sedimentation of the suspended multi-layered particles. Ifshaken, however, the viscosity of the suspension might transiently belowered so that it can easily be applied via a syringe-like oraldispenser. This behaviour can for example be reached by the mentionedmixture of hydrophilic and hydrophobic colloidal silica.

It is further preferred that the composition contains a flavoring agentin order to render the formulation attractive for the patient, e.g. ameat flavor to render it attractive to carnivorous animals like cats.

With respect to cilobradine hydrochloride it is preferred to suspend therespective multi-layered particles in the liquid composition to anextent of about 3.8% (w/v), resulting in a concentration of 2 mg/ml ofthe pharmaceutically active ingredient.

If the coated particles are to be incorporated into a liquid matrix, ithas to be ensured that the suspension medium does not interact with thefilm coating on the pellets in a way that would compromise the desireddrug release profile. This is possible by the addition of anotherprotective layer onto the surface of the particles, as explained aboveand/or by the addition of further excipients into the liquid matrix, aswill be explained below. It is especially preferred to combine therespective teachings.

Another preferred mode of the invention is a pharmaceutical compositionaccording to the invention in overall liquid form, which is an oilysuspension, more preferred an oily suspension comprising a viscosityenhancer selected from one or more of silicon dioxide, hydrophobicsilicon dioxide, EC (cellulose ether), poly(1-vinylpyrrolidin-2-one)(PVP), aluminium stearate, xanthan gum, carrageen, and/or starchderivatives.

Especially preferred are such overall liquid, oily pharmaceuticalcompositions that comprise a mixture of hydrophilic and hydrophobiccolloidal siliciumdioxide, preferably at a weight percent ratio of 0.5:1to 50:1, more preferred 1:1 to 25:1, more preferred 2:1 to 10:1, mostpreferred 2.25:1 to 5:1.

A person skilled in the art is able to vary the respectivesiliciumdioxide concentrations within these ranges. Regularly possibleand preferred is a ratio and content of both compounds that gives thesuspension a very advantageous physicochemical behavior, i.e. a highviscosity during storage and a lowered viscosity after shaking due tothe mechanical energy exerted by the shaking. This effect stabilizes thesuspension during its storage but allows that it can easily be appliedafter shaking, e.g. by a syringe or by dropwise addition to a foodpreparation etc.

Another preferred mode of the invention is a pharmaceutical compositionaccording to the invention in overall liquid form, which is an aqueoussuspension, more preferred an aqueous suspension comprising stabilisersselected from one or more of cellulose ethers, carbopol, xanthan gum,carrageen, microcrystalline cellulose.

Especially preferred are such overall liquid pharmaceutical compositionsthat comprise the pharmaceutically active ingredient in a finalconcentration of 0.1 to 20 mg/ml, preferred 0.5 to 5 mg/ml, morepreferred 0.75 to 4 mg/ml, most preferred 0.5 to 3 mg/ml.

This has turned out to be useful for the intended therapy, e.g. the onesthat are accessible by the preparations of the examples. The appropriateconcentration can be adapted by a person skilled in the art with respectto the intended treatment and the patient group to be treated.

Preferred embodiments of this aspect of the invention are pharmaceuticalcompositions according to the invention, wherein the pharmaceuticallyactive ingredient (a) (a DPP IV inhibitor) for the use for the treatmentof a metabolic disease is selected from1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthineor any appropriate form and/or salt thereof, preferably1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydro chloride.

In line with the explanations above, these compounds have turned out tobe very useful for the therapy of metabolic diseases of human and animalpatients, of diabetes, especially of diabetes type 2, and in a certaindosage range that is accessible by the formulation intermediatesaccording to the invention, i.e. by multi-layered particles according tothe invention.

Respectively preferred are the following modes of this aspect of theinvention:

-   -   pharmaceutical compositions according to this aspect, for the        treatment of an animal, preferably a mammal, more preferred a        predominantly carnivorous mammal, most preferred a cat (feline);    -   pharmaceutical compositions according to this aspect, for the        treatment of diabetes, preferably of diabetes type 2;    -   pharmaceutical compositions according to this aspect, in solid        form, comprising 2 to 50 mg per unit, more preferred 3 to 40 mg        per unit, even more preferred 4 to 30 mg per unit

Equally preferred embodiments of this aspect of the invention arepharmaceutical compositions according to the invention, wherein thepharmaceutically active ingredient ((3) (an i_(f)-channel blocker) forthe use for the treatment of a heart disease, especially heart failurevia the i_(f)-channel as target is selected from zatebradine(1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane),3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on,its enantiomer cilobradine((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on)or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), mostlypreferred cilobradine hydrochloride((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onhydrochloride).

In line with the explanations above, these compounds have turned out tobe very useful for the therapy of heart diseases, especially ofcongestive heart failure of human and animal patients, and in a certaindosage range that is accessible by the formulation intermediatesaccording to the invention, i.e. by multi-layered particles according tothe invention.

Respectively preferred are the following modes of this aspect of theinvention:

-   -   pharmaceutical compositions according to this aspect, for the        treatment of an animal, preferably a mammal, more preferred a        predominantly carnivorous mammal, most preferred a cat (feline);    -   pharmaceutical compositions according to this aspect, in overall        liquid form, comprising the pharmaceutically active ingredient        in a final concentration of 0.5 to 5 mg/ml, preferred 0.75 to 4        mg/ml, more preferred 0.5 to 3 mg/ml.

Equally preferred embodiments of this aspect of the invention arepharmaceutical compositions according to the invention, wherein thepharmaceutically active ingredient (γ) (a phosphodiesterase IIIinhibitor) for the use for the treatment of a heart disease viaphosphodiesterase III as target, is pimobendan((RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one).

A preferred mode of this aspect is such a pharmaceutical composition forthe treatment of an animal, preferably a mammal, more preferred apredominantly carnivorous mammal, most preferred a dog (canis) or a cat(feline).

Equally preferred embodiments of this aspect of the invention arepharmaceutical compositions according to the invention, wherein thepharmaceutically active ingredient (6) (a cyclooxygenase 2 inhibitor)for the use for the treatment of an inflammatory disease viacyclooxygenase 2 as target, is meloxicam4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide).

A preferred mode of this aspect is such a pharmaceutical composition forthe treatment of an animal, preferably a mammal, more preferred apredominantly carnivorous mammal, most preferred a dog (canis) or a cat(feline).

Equally preferred embodiments of this aspect of the invention arepharmaceutical compositions according to the invention, wherein thepharmaceutically active ingredient (ε) (a benzodiazepine receptoragonist) for the use for the treatment of a disease of the centralnervous system via the benzodiazepine receptor as target, is selectedfrom 1-(4-chlorophenyl)-4-piperidinoimidazolin-2-one and imepitoin(1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one),preferably imepitoin.

In line with the explanations above, these compounds have turned out tobe very useful for the therapy of central nervous system disorders likeepilepsy, especially idiopathic epilepsy, and behavioural abnormalities,esp. anxiety, of human and animal patients, and in a certain dosagerange that is accessible by multi-layered particles according to theinvention.

Respectively preferred are the following modes of this aspect of theinvention:

-   -   pharmaceutical compositions according to this aspect, for the        treatment of an animal, preferably a mammal, more preferred a        predominantly carnivorous mammal, most preferred a dog (canis);    -   pharmaceutical compositions according to this aspect, for the        treatment of epilepsy and/or anxiety, preferably of epilepsy,        more preferred of idiopathic epilepsy;    -   pharmaceutical compositions according to this aspect, that allow        the oral administration of up to 60 mg/kg per day, preferably 5        to 40 mg/kg per day;    -   pharmaceutical compositions according to this aspect, that are        administered not more than five times daily, preferably once or        twice daily.

Another aspect of the invention pertains to the package of an overallliquid, oily pharmaceutical composition according to the inventioncomprising a glass vial and the pharmaceutical composition filledtherein.

Especially this package form has turned out to be useful for the storageof overall liquid, oily pharmaceutical composition according to theinvention because they strongly inhibit the diffusion of humiditythrough the walls of the respective vial into the overall water-freepharmaceutical composition.

It is further preferred that a dark glass, e.g. green or even better:brown glass is used, in order to further protect the ingredients, e.g.against the light.

Appropriate sizes for such glass vials can be developed by a personskilled in the art with respect to the amount to be filled in, e.g. forsingle use, for providing an appropriate amount for the complete therapyof one patient or for the treatment of a patient group, for example abreed of domestic animals.

One subject of the invention pertains to pharmaceutical compositionscomprising cilobradine((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on),cilobradine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride), zatebradine(1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane),or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline) for use ina method for the treatment of a heart disease of an animal, preferably amammal, more preferred a predominantly carnivorous mammal, even morepreferred a cat (feline) or dog (canis), most preferred a cat (feline).

In line with the explanations above, cilobradine or cilobradinehydrochloride are preferred, more preferred is cilobradinehydrochloride.

In line with the explanations given above, it has been found by theinventors that especially this compound that addresses the i_(f)-channelas its respective target is highly advantageous for the treatment ofheart diseases of such animals.

Accordingly, another aspect of the invention is the use of cilobradine((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on),cilobradine hydrochloride((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride), zatebradine(1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane),or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline) in amethod for the treatment of a heart disease of an animal, preferably amammal, more preferred a predominantly carnivorous mammal, even morepreferred a cat (feline) or dog (canis), most preferred a cat (feline).

In line with the explanations above, cilobradine or cilobradinehydrochloride are preferred, more preferred is cilobradinehydrochloride.

According to a further aspect, it is preferred to use the multi-layeredparticles described above for the treatment of heart diseases,especially heart failure of companion animals, predominantly carnivorousanimals like cats (feline) or dogs (canine), e.g. by incorporation intoa respective medical formulation.

Preferred is the use of liquid pharmaceutical compositions with a finalconcentration of the active ingredient of 0.5 to 5 mg/ml, preferred 0.75to 4 mg/ml, more preferred 0.5 to 3 mg/ml.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventors to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Formulation of a Compound for the Treatment of Diabetes

An objective of this example was to produce a formulation of compound1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride, as disclosed e.g. by patent applicationPCT/EP2011/054440, in the form of a tablet with an overall weight of180-260 mg with a dose of 21.68 mg of1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydro chloride, which corresponds to 20 mg of the respective freebase.

A four-step process was applied as summarized in Table 2 and in moredetail below.

TABLE 2 Flow chart for the production of multi-layered particlescomprising 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrate asan active ingredient. starting step material coating result 1 inert coredrug layering with pharmaceu- IR1 pellets particles tically ingredientand HPMC 2 IR1 pellets drug layering with pharmaceu- IR2 pellets ticallyactive ingredient and HPMC 3 IR2 pellets seal coating with HPMC and SC(seal coated) PEG 6000 pellets 4 SC pellets taste masking coating withpoly- final multi-layered (meth)acrylate particleSteps 1 and 2: Drug Layering (Production of IR1 and IR2 Pellets)

Particles of microcrystalline cellulose of about 400 g with an averagediameter of 100 μm (100 μm Cellets®; purchased from Syntapharm; HarkeGroup, Mülheim an der Ruhr, Germany) were placed in a fluid bedapparatus (Glatt, Binzen, Germany). For the first layering step, amixture of 600 g of1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride and 90 g of HPMC (apparent viscosity 4.8-7.2 mPa*s at2% (w/v) in water at 20° C.; (commercially available under the tradename Pharmacoat® 606 from ShinEtsu, Tokyo, Japan), i.e. at a ratio ofabout 15% (w/w)), was dissolved in purified water at a concentration ofabout 20% (w/v) and sprayed onto the inert carrier material andsubsequently dried. According to the geometry of the apparatus, theresulting IR1 pellets were split into two fractions and treatedidentically according to step 2.

In step 2, 400 g of IR1 pellets were placed in the same fluid bedapparatus as before and sprayed with the same mixture of 600 g activeingredient and 90 g HPMC that was used in step 1. The total compositionof the resulting IR2 pellets is shown in Table 3.

TABLE 3 Composition of IR2 pellets comprising 1-[(3-cyano-pyridin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride as the active ingredient. Component Totalamount [% (w/w)] inert core particles (Cellets ® 100) 13.46 activeingredient 75.25 HPMC (Pharmacoat ® 606) 11.29Step 3: Seal Coating (Production of SC Pellets)

The resulting IR2 pellets of step 2 were covered by a protective layer(“seal coating”) to produce so-called SC pellets as follows: a mixtureof 168 g of HPMC (apparent viscosity 2.4-3.6 mPa*s at 2% (w/v) in waterat 20° C. (commercially available under the trade name Pharmacoat 603 ®from ShinEtsu, Tokyo, Japan), 21 g PEG 6000 and 50 g talc, dispersed inpurified water to yield about 11% (w/v) solids in the spraying liquid,was sprayed onto the IR2 pellets (600 g) in the same fluid bed apparatusas used for steps 1 and 2 and subsequently dried. The resulting totalcomposition of the SC pellets is given in Table 4.

TABLE 4 Composition of SC pellets comprising 1-[(3-cyano-pyridin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride as active ingredient. Component Totalamount [% (w/w)] inert core particles (Cellets ® 100) 10.77 activeingredient 60.19 HPMC (Pharmacoat ® 606) 9.03 HPMC (Pharmacoat ® 603)14.04 PEG 6000 1.77 Talc 4.20Step 4: Final Coating (Taste Masking; Production of Final Multi-LayeredParticles), Aqueous Coating

As in the steps before the following mixture was added to the SCpellets: 62.5% (w/w) basic butylated methacrylate copolymer (certainpoly(meth)acrylate, which is a cationic copolymer based ondimethylaminoethyl methacrylate, butyl methacrylate, and methylmethacrylate with a ratio of 2:1:1 and a molecular weight of about47,000 g/mol (sold under the trade name Eudragit® E PO by Evonik Röhm,Darmstadt, Germany), 6.2% (w/w) sodium lauryl sulfate, 9.3% (w/w)stearic acid and 21.9% (w/w) magnesium stearate, dispersed in purifiedwater to yield approximately 16% (w/v) solids in the spraying liquid.

This process was carried out in four different modes, differing withrespect to the thickness of the added final coating:

-   (a) stopping the process after adding 50% final coating material,    calculated on the weight amount of SC pellets placed in the fluid    bed chamber (50% coating level)-   (b) stopping the process after adding 100% final coating material,    respectively (100% coating level)-   (c) stopping the process after adding 150% final coating material,    respectively (150% coating level)-   (d) stopping the process after adding 200% final coating material,    respectively (200% coating level)

Accordingly, the final coating consists of a mixture of basic butylatedmethacrylate copolymer, sodium lauryl sulphate, stearic acid, andmagnesium stearate in the relative portions of 62.5/6.2/9.3/21.9 (all in% (w/w)) with around 50%, 100%, 150% and 200% solid deposit (weightpercentage based on the amount of “SC pellets” starting material).

The total composition of final taste masked multi-layered particlescomprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride as the active ingredient, as produced by steps 1 to 4with stopping the final coating process after adding 200% final coatingmaterial (i.e. mode (d); 200% coating level), is given in Table 5.

TABLE 5 Total composition of final taste masked multi-layered particlescomprising 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochlorideas the active ingredient. Amount Component [% (w/w)] Function inert coreparticles (Cellets ® 100) 3.59 Carrier pharmaceutically activeingredient 20.06 Drug layer HPMC (Pharmacoat ® 606) 3.01 HPMC(Pharmacoat ® 603) 4.69 Seal coating PEG 6000 0.59 Talc 1.40 basicbutylated methacrylate copolymer 41.66 Final coating Sodiumdodecylsulfate 4.15 (taste masking) Stearic acid 6.26 Magnesium stearate14.59

Even with this highly water soluble drug, all drug layering and polymercoating steps could be performed using aqueous as well as organicsolvent coating processes without the bitter active ingredient migratinginto the outer polymer layers. This lack of admixing was proven by SEMcoupled with x-ray/EDS (Energy Dispersive X-ray analysis) which showedthat no chloride ions stemming from the pharmaceutically activeingredient were detected in the final outer coating layer.

In a further control experiment, the raman spectra of components of theparticle were measured. It was found that the final coating layercomprising the butylated methacrylate copolymer at 200% coating levelshowed a thickness of between 77 and 119 μm±10 μm.

Variation of Step 4: Final Coating (Taste Masking Coating; Production ofFinal Multi-Layered Particles), Organic Solvent Coating

In a variation of the aqueous coating, step 4 was repeated identically,except that an organic solvent coating was applied. For this purpose,444 g basic butylated methacrylate copolymer in powder form (Eudragit® EPO) and 186 g magnesium stearate were dissolved in isopropanol/acetone(volume ratio 3:2) to yield approximately 17% (w/v) solids in thespraying liquid. The final coating material was sprayed onto the SCpellets, which had been placed in the fluid bed apparatus like before.

Again, the process was carried out in 4 different modes, differing withrespect to the thickness of the added final coating, leading to thecomparably composed materials (a) to (d), i.e. to multi-layeredparticles comprising a final coating consisting of basic butylatedmethacrylate copolymer and magnesium stearate in a 70.5/29.5 ratio (allin % (w/w)) with around 50%, 100%, 150% and 200% solid deposit (weightpercentage based on the amount of “SC pellets” starting material).

Dissolution Experiments after Final Aqueous Coating

The final multi-layered particles produced according to the above steps,with step 4 comprising the aqueous coating process, were analyzed withrespect to their dissolution characteristics.

The respective particles, prototypes (a), (b), (c), and (d), differingwith respect to the thickness of the final coating level, were analyzedin a dissolution apparatus 2, according to European Pharmacopoeia (Ph.Eur.), using either Na₂HPO₄ buffer (pH 6.8) or hydrochloric acid (pH 1)as dissolution medium. The dissolution samples were analyzed for theactive ingredient via HPLC/UV.

The dissolution experiment was carried out at two different pH values,at pH 6.8 and pH 1, to mimic the pH environment in the patient's oralcavity and stomach, respectively. The result is given in Table 6 andcorresponding FIG. 1. FIG. 1A shows the measured dissolution curve at pH1 and FIG. 1B shows the measured dissolution curve at pH 6.8. The amountof the released drug was normalized to the theoretical drug content inthe sample, which allows maximal values higher than 100% and arecomparable with each other for each curve. The result becomes clear withrespect to the finally reached plateau for each curve (whichtheoretically can also be used for the definition of 100% release).

TABLE 6 Drug release from multi-layered particles comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride finally coated with basicbutylated methacrylate copolymer at 50-200% coating level (aqueousspraying process) at pH 1 and pH 6.8 (mean, n ≧ 3) measured values arethe cumulative percentage of released material after the respective time(visualized in FIGS. 1A and 1B). Time 50% 100% 150% 200% [min] coatingcoating coating coating pH 1 0 0 0 0 0 5 87.0 81.0 69.0 78.8 10 87.182.4 92.3 83.4 15 87.6 92.1 113.7 101.8 30 87.9 91.9 124.6 104.9 45 87.993.7 131.3 107.4 60 88.0 93.9 135.9 108.7 90 88.0 93.2 145.0 110.4 pH6.8 0 0 0 0 0 5 82.7 31.7 17.1 5.8 10 85.9 61.4 37.6 14.3 15 86.7 72.352.8 22.2 30 87.6 80.8 77.8 53.0 45 88.2 83.0 86.8 70.4 60 88.6 83.589.5 77.0 90 89.7 84.0 91.5 83.4Dissolution Experiments after Final Organic Solvent Coating

The final multi-layered particles produced according to the steps beforewith step 4 varied with respect to the coating process, i.e. the variantof organic solvent coating, were also analyzed with respect to theirdissolution characteristics.

For this purpose, the respective particles, prototypes (a), (b), (c) and(d), differing with respect to the thickness of the final coating level,were treated as before. The dissolution experiment was again carried outat the two different pH values of pH 6.8 and pH 1. The result is givenin Table 7 and corresponding FIG. 2. FIG. 2A shows the measureddissolution curve at pH 1 and FIG. 2B shows the measured dissolutioncurve at pH 6.8.

TABLE 7 Drug release from multi-layered particles comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride finally coated with basicbutylated methacrylate copolymer at 50-200% coating level (organicspraying process) at pH 1 and pH 6.8 (mean, n ≧ 3) measured values arethe total percentage of released material after the respective time(visualized in FIGS. 2A and B). Time 50% 100% 150% 200% [min] coatingcoating coating coating pH 1 0 0 0 0 0 5 100.7 89.1 54.0 54.0 10 92.281.5 86.0 86.0 15 92.6 85.9 112.1 112.1 30 92.8 96.6 112.8 112.8 45 92.798.4 116.5 116.5 60 92.6 100.0 116.6 116.6 90 92.4 99.1 116.6 116.6 pH6.8 0 0 0 0 0 5 19.9 6.7 4.7 4.3 10 64.9 16.2 6.9 5.6 15 82.5 31.3 10.47.4 30 92.5 74.9 32.7 16.3 45 94.0 86.5 63.6 34.3 60 94.7 90.4 77.5 56.490 95.1 92.7 87.6 74.6Result of the Dissolution Experiments

Both of these data sets reveal that multi-layered particles coated withbasic butylated methacrylate copolymer exhibit an increasingly delayedrelease at pH 6.8, depending on the coating thickness, and an immediaterelease at pH 1. Accordingly, they are able to mask the taste of apharmaceutically active ingredient in the oral cavity (pH 6.8) whilefacilitating immediate drug release in the stomach (pH 1).

This is true for the particles that have been coated by an aqueouscoating process with the material basic butylated methacrylatecopolymer, sodium lauryl sulphate, stearic acid and magnesium stearatein the 62.5/6.2/9.3/21.9 mixture (all in % (w/w) as well as for theparticles that have been coated by an organic solvent coating processwith the material basic butylated methacrylate copolymer and magnesiumstearate in a 70.5/29.5 ratio (all in % (w/w)).

Especially particles coated at coating levels of about 200% show thedesired drug release profile, irrespective of the solvent used for thefinal coating process.

Tablet Formulation

Multi-layered particles comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthinemonohydrochloride coated with basic butylated methacrylate copolymer ata 200% coating level according to the aqueous coating proceduredescribed before, were admixed to a complete tablet formulation,according to the composition outlined in table 8. The listed ingredientswere bought from commercial providers. Colloidal silicium dioxide wasbought under the trade name Aerosil® 200 from Evonik Röhm, Darmstadt,Germany. Cross-linked PVP was bought under the trade name Kollidon® CLfrom BASF, Ludwigshafen, Germany).

TABLE 8 Composition of tableting mix containing taste masked multi-layered particles comprising 1-[(3-cyano-pyridin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride coated with basic butylatedmethacrylate copolymer at a 200% coating level. Amount Component [%(w/w)] Function final multi-layered particles comprising 49.78 APIcontaining pharmaceutically active ingredient and intermediate a 200%coat Mannitol 27.42 filler/binder Maize starch 9.50 filler/bindercross-linked PVP (Kollidon ® CL) 1.50 disintegrant Meat flavor 10.00flavoring agent Iron oxide yellow 0.35 pigment Iron oxide brown 0.35pigment colloidal silicium dioxide (Aerosil ® 0.30 glidant 200)Magnesium stearate 0.80 lubricant

All components except for the multilayered particles were screenedtogether, placed in a polyethylene bag and premixed by hand. Themultilayered particles were screened separately. The components weresubsequently put in a 40 l mixing container and mixed to yield the finaltableting mix. By use of a standard apparatus the tableting mix wascompressed to tablets with 5, 10 and 20 mg of the pharmaceuticallyactive ingredient.

Dissolution Experiments with the Tablet

The tablets produced as described before were analyzed in a dissolutionexperiment. This dissolution experiment was carried out as describedbefore for the particles, again at the two different pH values of pH 6.8and pH 1. As a control, the multi-layered particles comprising a 200%poly(meth)acrylate aqueous coating as described before were measured inthe same way. The measurement aimed at the detection of the releaseddrug, quantified by HPLC/UV (percentage in relation to the total amountof the active ingredient in the tablet).

The result is given in following table 9 and corresponding FIG. 3.

TABLE 9 Drug release from multi-layered particles comprising1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]- xanthinemonohydrochloride coated with basic butylated methacrylate copolymer ata 200% coating level at pH 1 and pH 6.8 and of the derived tablets (mean± SD, n ≧ 3); measured values are the total percentage of releasedactive compound after the respective time (visualized in FIG. 3). Time[min] % released at pH 1 % released at pH 6.8 Multi-layered particles 00 0 5 106.9 0 10 110.5 0.1 15 108.1 1.3 30 108.2 34.7 45 108.6 90.4 60110.2 106.2 90 111.2 111.7 Tablets 0 0 0 5 24.9 1.8 10 42.9 3.5 15 59.25.7 20 73.5 8.2 30 91.9 14.7 45 101.9 29.3

As can be seen from these data, the release of the active ingredientfrom tablets containing the drug loaded pellets is slower than fromuncompressed pellets at pH 6.8 as well as at pH 1, due to thedisintegration of the tablet.

Further, the film coating on the multi-layered particles is mechanicallystable enough to stay intact throughout the tableting process and canprovide taste and/or odor masking of the drug in a tablet formulation.

EXAMPLE 2 Formulation of a Compound for the Treatment of a Heart Disease

This example aims at the formulation of compound(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onhydrochloride in liquid form.

For the production of multi-layered particles for incorporation into aliquid dosage form, a three-step process was applied which process issummarized in table 10.

TABLE 10 Flow chart for the production of multi-layered particlesaccording to the invention, comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride as activeingredient. starting step material coating result 1 inert core druglayering with pharmaceu- IR pellets particles tically active ingredientand HPMC/magnesium stearate 2 IR pellets seal coating with PVP K 30/ SC(seal coated) Talc/colloidal siliciumdioxide pellets 3 SC pellets tastemasking coating with final multi-layered EC/HPMC/magnesium stearate/particle colloidal siliciumdioxideStep 1: Drug Layering

Like in example 1 microcrystalline cellulose particles with an averagediameter of 100 μm were used as starting material and layered withactive ingredient and binder, using water as solvent. The layer materialconsisted of 66.6% (w/w) of the pharmaceutically active ingredient,31.7% (w/w) HPMC (Pharmacoat® 606; see example 1) and 1.7% (w/w)magnesium stearate, dispersed in purified water to yield approx. 19%solids in the spraying liquid.

The resulting composition of the produced IR pellets is given in table11.

TABLE 11 Composition of IR pellets comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochlorideComponent Amount [% (w/w)] inert core particles (Cellets ® 100) 80.94pharmaceutically active ingredient 12.70 HPMC (Pharmacoat ® 606) 6.04Magnesium stearate 0.32Step 2: Seal Coating

The IR pellets produced in step 1 were further processed in the sameapparatus by spraying the seal coating onto the IR pellets. The materialfor the seal coating was composed of PVP K 30 (commercially available bythe provider BASF, Ludwigshafen, Germany, under the trade name Kollidon®30/talc, at a weight-percent ratio of 75.4:22.5, dispersed in a 94:6mixture (m/m) of acetone and ethanol. 0.5% (w/w) of a highly disperse(colloidal) silicium dioxide (Aerosil® 200, commercially available fromEvonik) was added by an additional (intermediate step) to the sealcoated material after the application of the PVP K 30/talc mixture anddrying of the organic solvent.

The total composition of the SC (seal coated) pellets yielded in thisstep (cilobradine seal coated pellets) is given in table 12.

TABLE 12 Composition of SC pellets comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochlorideComponent Amount [% (w/w)] IR pellets comprising the pharmaceutically76.54 active ingredient PVP K 30 (Kollidon ® 30) 17.67 Talc 5.29colloidal silicium dioxide (Aerosil ® 200) 0.5Step 3: Final Coating (Taste Masking Coating)

The SC pellets produced in step 2 were further processed in the sameapparatus by spraying the final coating onto the SC pellets. Thematerial for the final taste and/or odor masking coating was composed ofEC/HPMC/magnesium stearate at a weight-percent ratio of 55.2:23.8:19.8(the ratio of EC/HPMC in the film coating being about 70:30). For thispurpose, EC, HPMC and magnesium stearate were dispersed in a 1:1 mixture(v/v) of methanol and dichloromethane, and sprayed onto the SC pellets.

The coating was applied to a thickness of 75% based on the initialamount of SC pellets.

Like in step 2, 0.5% of the colloidal silica of Aerosil® 200 were addedto the final product before sieving.

The chosen EC was Ethocel® 45 cps STD Premium, commercially availablefrom Dow Chemical, Schwalbach, Germany. The chosen HPMC for this layerwas Methocel® E5 Premium LV, commercially available from Dow Chemical.Aerosil® 200 was provided by Evonik.

The overall composition of the final multi-layered particles is given intable 13.

TABLE 13 Composition of final multi-layered particles comprising (+)-3-[N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochlorideComponent Amount [% (w/w)] SC pellets comprising the pharmaceutically56.86 active ingredient EC 23.86 HPMC 10.25 Magnesium stearate 8.54colloidal silicium dioxide (Aerosil ® 200) 0.5

Table 14 discloses the detailed overall composition of taste maskedmulti-layered particles comprising(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onhydrochloride, as produced according to steps 1-3 of this example, alongwith the assumed physicochemical function of the respective material.

TABLE 14 Detailed composition of final multi-layered particlescomprising(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-onhydrochloride Amount [% Component (w/w)] Function inert core particles(Cellets ® 100) 35.23 Carrier pharmaceutically active ingredient 5.53Drug layer cilobradine (calculated as hydrochloride) HPMC 2.63Polyvinylpyrrolidone K 30 10.05 Seal coating Talc 3.01 Ethylcellulose23.86 Final coating HPMC 10.25 (taste masking) Magnesium stearate 8.68colloidal silicium dioxide 0.78 Reduction of electro- (Aerosil ® 200)static charging in seal coating and final coatingDissolution Experiments

The multi-layered particles produced in this example were tested withrespect to their dissolution properties in the same way as the particlesaccording to example 1, again at the two different pH values of 6.8and 1. Measured values are the total percentage of released materialafter the respective time, normalized to the theoretical drug content.The result is given in table 15 and visualized in FIG. 4.

TABLE 15 Drug release from multi-layered particles comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-onhydrochloride finally coated with EC/HPMC 70:30 at pH 1 and pH 6.8(mean, n ≧ 3; visualized in FIG. 4) Time [min] % released at pH 1 %released at pH 6.8 0 0.0 0.0 5 19.4 7.2 10 25.6 9.4 30 53.4 16.7 45 72.923.2 60 87.2 30.9 90 103.4 48.3

According to these data, the dissolution from EC/HPMC coated pellets isdelayed, therefore providing efficient taste and/or odor masking of thebitter drug(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onhydrochloride. This could be verified by acceptance tests withlaboratory cats with the derived completely formulated liquidcomposition prepared as described below.

Usually, EC/HPMC films show a sustained release behavior that isindependent of pH. In this case, however, the product surprisinglyshowed a slower release at pH 6.8 which is favorable with regards to theinvention, i.e. providing efficient taste masking in the oral cavity anda faster release in the acidic stomach. This may be explained by thelipophilicity profile of the active substance cilobradine HCl, which isslightly more lipophilic at neutral pH values. This, together with thecoating applied, may have led to a slower release.

Liquid Pharmaceutical Composition

In order to prepare a liquid pharmaceutical composition, the finalmulti-layered particles comprising the active ingredient ciloradineprepared in the way explained above were incorporated into an oilyliquid. This liquid consisted of a mixture of Medium chain triglycerides(Miglyol® 821, bought from Sasol, Hamburg, Germany), a hydrophiliccolloidal silicium dioxide (Aerosil® 200, Evonik), a hydrophobiccolloidal silicium dioxide (Aerosil® R972, Evonik) and meat flavor, atthe weight ratios listed in table 16.

TABLE 16 Liquid pharmaceutical composition comprising multi-layeredparticles comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride Amount Component [% (w/w)]medium chain triglycerides 93.23 (Miglyol ® 821) hydrophilic colloidalsilicium dioxide (Aerosil ® 200) 4.44 hydrophobic colloidal siliciumdioxide (Aerosil ® R972) 1.82 meat flavor 0.51

The multi-layered particles as produced according to step 3 weresuspended in the mentioned liquid composition to an amount of about 3.8%(w/v), resulting in a concentration of 2 mg/ml of the pharmaceuticallyactive ingredient (calculated as hydrochloride).

It has been found that the composition of the oily solvent, especiallythe mixture of hydrophilic and hydrophobic colloidal silica, ensures anappropriate viscosity behaviour of the suspension that remains more orless unchanged over the storage period. During storage, the suspensionexhibits a high viscosity, preventing sedimentation of the suspendedcilobradine pellets. If shaken, the viscosity of the suspension istransiently lowered so that it can easily be applied via a syringe-likeoral dispenser.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by thefollowing claims.

To the extent that the patents and publications referred to hereinprovide exemplary procedural or other details supplementary to those setforth herein, all of these patents and publications are specificallyincorporated herein by reference. Nothing herein is to be construed asan admission that the invention is not entitled to antedate suchdisclosure by virtue of prior invention.

What is claimed is:
 1. A pharmaceutical composition comprising a tastemasked multi-layered particle, the multi-layered particle comprising: a)an inert core, b) at least one coating layer that comprises apharmaceutically active ingredient and a binder, c) an intermediatecoating layer (seal coating) free from a low molecular weightwater-soluble ionic compound and comprising a water-solublepharmaceutical film-forming compound, selected from the group consistingof hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG)poly(1-vinylpyrrolidin-2-one) (PVP), and any combination thereof, and d)an outer coating layer (final or taste masking coating) free from a lowmolecular weight water-soluble ionic compound and comprising (i) apoly(meth)acrylate or (ii) a mixture comprising 60-90% (w/w)ethylcellulose (EC) and 10-40% (w/w) hydroxypropyl methylcellulose(HPMC), wherein the pharmaceutically active ingredient is water-solubleand comprises either at least one basic group and/or a bitter taste;wherein the pharmaceutical composition is in solid form with a mass of20 to 4000 mg per unit.
 2. The pharmaceutical composition of claim 1,further comprising the pharmaceutically active ingredient in a finalconcentration of 0.1 to 1000 mg per unit.
 3. The pharmaceuticalcomposition of claim 1 in the form of a tablet with one or more scorelines to be split into pieces.
 4. The pharmaceutical composition ofclaim 1 in a liquid form.
 5. The pharmaceutical composition of claim 4,wherein the liquid form comprises an oily suspension comprising aviscosity enhancer selected from the group consisting of silicondioxide, hydrophobic silicon dioxide, EC (cellulose ether),poly(1-vinylpyrrolidin-2-one) (PVP), aluminium stearate, xanthan gum,carrageen, starch derivatives, and one or more combinations thereof. 6.The pharmaceutical composition of claim 5, further comprising a mixtureof hydrophilic and hydrophobic colloidal silicium dioxide.
 7. Thepharmaceutical composition of claim 6 which is an aqueous suspensioncomprising stabilizers selected from one or more of cellulose ethers,carbopol, xanthan gum, carrageen, microcrystalline cellulose.
 8. Thepharmaceutical composition of claim 4, further comprising thepharmaceutically active ingredient in a final concentration of 0.1 to 20mg/ml.
 9. A package of an overall liquid, oily pharmaceuticalcomposition according to claim 5 comprising a glass vial and thepharmaceutical composition filled therein.